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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.

 

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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.

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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.  

“This drug might be harmful!  Why was it approved?”  What the news reports fail to tell us.

Posted by Brook White on Thu, Apr 19, 2018 @ 08:39 AM
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Jack Modell, MD, Vice President and Senior Medical OfficerJack Modell, MD, Vice President and Senior Medical Officer is a board-certified psychiatrist with 35 years’ of experience in clinical research and patient care including 15 years’ experience in clinical drug development. He has led successful development programs and is a key opinion leader in the neurosciences, has served on numerous advisory boards, and is nationally known for leading the first successful development of preventative pharmacotherapy for the depressive episodes of seasonal affective disorder.

David Shoemaker, PhD, Senior Vice President, R&DDavid Shoemaker, PhD, Senior Vice President R&D, has extensive experience in the preparation and filing of all types of regulatory submissions including primary responsibility for four BLAs and three NDAs.  He has managed or contributed to more than two dozen NDAs, BLAs, and MAAs and has moderated dozens of regulatory authority meetings.  

Once again, we see news of an approved medication* being linked to bad outcomes, even deaths, and the news media implores us to ask:  

drugs and biologics in the news“How could this happen?”
“Why was this drug approved?”
“Why didn’t the pharmaceutical company know this or tell us about it?”
“What’s wrong with the FDA that they didn’t catch this?”
“Why would a drug be developed and approved if it weren’t completely safe?”

And on the surface, these questions might seem reasonable.  Nobody, including the drug companies and FDA, wants a drug on the market that is unsafe, or for that matter, wants any patient not to fare well on it.  And to be very clear at the outset, in pharmaceutical development, there is no room for carelessness, dishonesty, intentionally failing to study or report suspected safety signals, exaggerating drug benefits, or putting profits above patients – and while there have been some very disturbing examples of these happening, none of this should ever be tolerated.  But we do not believe that the majority of reported safety concerns with medications are caused by any intentional misconduct or by regulators failing to do their jobs, or that a fair and balanced portrayal of a product’s risk-benefit is likely to come from media reports or public opinion alone.

While we are not in a position to speculate or comment upon the product mentioned in this article specifically, in most cases we know of where the media have reported on bad outcomes for patients taking a particular medication, the reported situations, while often true, have rarely been shown to have been the actual result of taking the medication; rather, they occurred in association with taking the medication.  There is, of course, a huge difference between these two, with the latter telling us little or nothing about whether the medication itself had anything to do with the bad outcome.  Nonetheless, the news reports, which include catchy headlines that disparage the medication (and manufacturer), almost always occur years in advance of any conclusive data on whether the medication actually causes the alleged problems; and in many cases, the carefully controlled studies that are required to determine whether the observed problems have anything directly to do with the medication eventually show that the medication either does not cause the initially reported outcomes, or might do so only very rarely.  Yet the damage has been done by the initial headlines:  patients who are benefiting from the medication stop it and get into trouble because their underlying illness becomes less well controlled, and others are afraid to start it, thus denying themselves potentially helpful – and sometimes lifesaving – therapy.  And ironically, when the carefully controlled and adequately powered studies finally do show that the medication was not, after all, causing the bad outcomes, these findings, if reported at all, rarely make the headlines. 

Medications do, of course, have real risks, some serious, and some of which might take many years to become manifest.  But why take any risk?  Who wants to take a medication that could be potentially harmful?  If the pharmaceutical companies have safety as their first priority, why would they market something that they know carries risk or for which they have not yet fully assessed all possible risks?  There’s an interesting parallel here that comes to mind.  I recently airplane-1heard an airline industry representative say that the airlines’ first priority is passenger safety.  While the U.S. major airlines have had, for decades, a truly outstanding safety record, could safety really be their first priority?  If passenger safety were indeed more important than anything else, no plane would ever leave the gate; no passengers would ever board.  No boarding, no leaving, and no one could ever possibly get hurt.  And in this scenario, no one ever flies anywhere, either.  The airlines’ first priority has to be efficient transportation, though undoubtedly followed by safety as a very close second.  Similarly, the pharmaceutical industry cannot put guaranteed safety above all else, or no medications would ever be marketed.  No medications and no one could ever get hurt.  And in this scenario, no one ever gets treated for illnesses that, without medications, often harm or kill.  In short, where we want benefit, we must accept risks, including those that may be unforeseeable, and balance these against the potential benefits.

OK then:  so bad outcomes might happen anyway and are not necessarily caused by medication, worse outcomes can happen without the medications, and we must accept some risk.  But isn’t it negligent of a pharmaceutical company to market a medication before they actually know all the risks, including the serious ones that might only happen rarely?  Well, on average, a new medicine costs nearly three-billion dollars and takes well over a decade to develop, and it is tested on up to a few thousand subjects.  But if a serious adverse event did not occur in the 3000 subjects who participated in the clinical trials to develop the medicine, does this show us that the medicine is necessarily safe and unlikely to ever harm anybody?  Unfortunately, it does not.  As can be seen by the statistical rule of three**, this can only teach us that, with 95% confidence, the true rate of such an event is between zero and 1/1000.  And while it may be comforting that a serious event is highly unlikely to occur in more than 1/1000 people who take the medication, if the true rate of this event is, let’s say, even 1/2000, there is still greater than a 90% chance that a serious adverse event will occur in at least one person among the first 5000 patients who take the medication!  Such is the nature of very low frequency events over thousands of possible ways for them to become manifest.

So why not study the new medication in 10,000 subjects before approval, so that we can more effectively rule out the chances of even rarer serious events?  There is the issue of cost, yes; but more importantly, we would now be extending the time to approval for a new medicine by several additional years, during which time far more people are likely to suffer by not having a new and needed treatment than might ever be prevented from harm by detecting a few more very rare events.  There is a good argument to be made that hurting more people by delaying the availability of a generally safe medication to treat an unmet medical need in an effort to try to ensure what might not even be possible – that all potential safety risks are known before marketing – is actually the more negligent course of action.  It is partly on this basis that the FDA has mechanisms in place (among them, breakthrough therapy, accelerated approval, and priority review) to speed the availability of medications that treat serious diseases, especially when the medications are the first available treatment or if the medication has advantages over existing treatments.  When these designations allow for a medication to be marketed with a smaller number of subjects or clinical endpoints than would be required for medications receiving standard regulatory review, it is possible that some of these medications might have more unknown risks than had they been studied in thousands of patients.  In the end, however, whatever the risks – both known and unknown – if we as a society cannot accept them, then we need to stop the development and prescribing of medicines altogether.  

*Neither of the authors nor Rho was involved in the development of the referenced product.  This post is not a comment on this particular product or the referenced report, but rather a response to much of the media coverage of marketed drugs and biologics more broadly.

**In statistical analysis, the rule of three states that if a certain event did not occur in a sample with n subjects, the interval from 0 to 3/n is a 95% confidence interval for the rate of occurrences in the population.  https://en.wikipedia.org/wiki/Rule_of_three_(statistics)  

The probability that no event with this frequency will occur in 5000 people is (1 - .005)5000, or about 0.082.

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505(b)(2) vs ANDA: How Complex Drugs Fit In

Posted by Brook White on Tue, Feb 20, 2018 @ 08:42 AM
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Choosing the Appropriate New Drug Application and Corresponding Abbreviated Development Pathway

Samantha Hoopes, PhD, RAC Integrated Product Development AssociateSamantha Hoopes, PhD, RAC is an Integrated Product Development Associate 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.

Sheila Bello-Irizarry, PhD, RAC, Research ScientistSheila Bello-Irizarry, PhD, RAC, Research Scientist, is actively involved in protocol development, orphan-drug designation applications, and regulatory submissions including INDs and NDAs/BLAs. Her therapeutic area experience includes infectious diseases, immunology, vaccines, lung biology, musculoskeletal, and antibody-mediated therapy.  She contributed to developing vaccine candidates against malaria and MRSA infections and to the understanding of inflammatory processes during lung fungal infections.

regulatory pathways--ANDA and 505(b)(2)With the confirmation of a new Food and Drug Administration (FDA) Commissioner, Scott Gottlieb, M.D., in 2017, we have seen some changes in the regulatory environment with a new Drug Competition Action Plan and FDA draft guidances focused on introducing more competition into the drug market with the goal of increasing access to drugs that consumers need.  These guidance documents are meant to provide information on abbreviated approval pathways and provide clarity on the regulatory pathway for complex generic drugs in order to speed approval allowing for more competition in the market place, which may impact pricing.  

While it is important to understand how to navigate the complex generic drug approval pathway, it is first necessary to determine whether your drug product should be submitted as an abbreviated new drug application (ANDA) for approval as a generic or if it requires submission of a 505(b)(2) new drug application.  This particular issue is addressed in a new draft guidance, published 13 October 2017, “Determining Whether to Submit an ANDA or a 505(b)(2) Application.”  The draft guidance defines an ANDA as an application for a duplicate (same with respect to their active ingredient[s], dosage form, route of administration, strength, previously approved conditions of use, and labeling [with certain exceptions]) of a previously approved drug product that relies on FDA’s findings that the previously approved drug product, the reference listed drug, is safe and effective.  An ANDA may not be submitted if studies are necessary to establish the safety and effectiveness of the proposed product.  A 505(b)(2) application contains full reports of safety and effectiveness, but one or more of the investigations relied upon by the applicant for approval were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted  [Guidance for Industry:  Applications Covered by Section 505(b)(2)]. 

The draft guidance outlines regulatory considerations for ANDA and 505(b)(2) applications as described below.  FDA will generally refuse to file a 505(b)(2) application for a drug that is a duplicate of a listed drug and eligible for approval via an ANDA.  An applicant may submit a suitability petition (21 CFR 314.93) to the FDA requesting permission to submit an ANDA, known as a petitioned ANDA, for a generic drug product that differs from the RLD in its dosage form, route of administration, strength or active ingredient (in a product with more than one active ingredient).  The FDA will not approve a suitability petition if determined that safety and effectiveness of the proposed changes from the reference listed drug cannot be adequately evaluated without data from investigations that exceed what may be required for an ANDA or the petition is for a drug product for which a pharmaceutical equivalent has been approved in an NDA.  The FDA will not accept an ANDA for filing for a product that differs from the reference listed drug until the suitability petition has been approved.

In some circumstances, an applicant may seek approval for multiple drug products containing the same active ingredient(s), known as bundling, when some of the products would qualify for approval under the 505(b)(2) pathway and some of the product would qualify for approval under the ANDA pathway.  The FDA allows the applicant to submit one 505(b)(2) application for all such multiple drug products that are permitted to be bundled.  An example referenced in the draft guidance where bundling into one 505(b)(2) submission would be allowed includes an applicant seeking approval of multiple strengths of a product where only some of which are listed in the Orange Book, as reference listed drugs. 

formal meetings with FDASeveral draft guidance documents have recently focused on complex generic drug products.  A draft guidance titled “Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA” was issued in October 2017 to provide ANDA applicants information on preparing and submitting meeting requests and meeting materials for complex generic drug products.  Complex products are defined as 1)  complex active ingredients, complex formulations, complex routes of delivery, complex dosage forms, 2)  complex drug-device combination products, or 3) other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement.  The guidance describes 3 types of meetings for complex products that may be submitted as an ANDA:  product development meetings, pre-submission meetings, and mid-review-cycle meetings. The draft guidance include details for how it is determined if meetings are granted and the review timeframe goals for FY2018 through FY2022.  

A draft guidance “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin” also issued in October 2017, focuses on helping applicants determine if certain complex products, synthetic peptides, that refer to a previously approved peptide drug product of recombinant deoxyribonucleic acid (rDNA) origin should be submitted as an ANDA.  In the past, analytical methods have not been capable of adequately characterizing peptide products for submission in an ANDA; however with advances in scientific technology, FDA now considers it possible to demonstrate that the active ingredient in a proposed generic synthetic peptide is the same as the active ingredient in the reference listed drug of rDNA origin.  While this guidance pertains to some specific synthetic peptides, Dr. Gottlieb addressed (FDA Voice, 02 October 2017) this general issue stating that “a further barrier to generic competition for certain complex drug products is the lack of established methods for showing the sameness of the active ingredient of a proposed generic drug to a brand-name drug for certain complex drugs” and “over the next year, FDA’s generic drug regulatory science program will work to identify gaps in the science and develop more tools, methods, and efficient alternatives to clinical endpoint testing, where feasible.”  These efforts are meant to encourage and facilitate complex generic drug development.  Additional guidance documents will continue to be released regarding specific types of complex drug products.

Additionally, a draft guidance released on 03 January 2018 “Good ANDA Submission Practices,”addresses common, recurring deficiencies seen in ANDAs that may lead to delay in approval.  Common deficiencies include not correctly addressing patent and exclusivity information for the RLD, not providing adequate and properly prepared clinical summary data tables for bioequivalence studies, and not submitting draft container and carton labels with an accurate representation of the formatting that will be used for the final printed labels.  In a statement from Dr. Gottlieb, “it currently takes on average about 4 cycles for an ANDA to reach approval – not necessarily because the product will not meet our standards, but sometimes because the application is missing the information necessary to demonstrate that it does” (Press Release 03 January 2017).  This guidance as well as a new manual of policies and procedures (MAPP:  Good Abbreviated New Drug Application Assessment Procedures) aim to help reduce the number of review cycles ANDAs undergo prior to approval.  

These recently released draft guidance documents provide clarity on abbreviated approval pathways and highlight priorities of the FDA to increase competition in the marketplace with a focus on speeding generic approvals, including complex generic drug products.  

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Revised Draft Guidance:  Formal Meetings with the FDA for Drug Products

Posted by Brook White on Wed, Jan 17, 2018 @ 10:52 AM
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Samantha Hoopes, PhD, RAC, Integrated Product Development AssociateSamantha Hoopes, PhD, RAC is an Integrated Product Development Associate 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.

David Shoemaker, PhD, Senior Vice President R&DDavid Shoemaker, PhD, Senior Vice President R&D, has extensive experience in the preparation and filing of all types of regulatory submissions including primary responsibility for four BLAs and three NDAs.  He has managed or contributed to more than two dozen NDAs, BLAs, and MAAs and has moderated dozens of regulatory authority meetings.  

On 29 December 2017, the FDA released a revised draft guidance “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.”  This draft guidance will replace the previous draft guidance posted in 2015 on this topic.  According to the draft guidance, from this point in time there will be 4 types of formal meetings with FDA staff:  

  • Type A
  • Type B
  • Type B (end of phase [EOP])
  • Type C

An overview of each type of meeting and the changes from the previous version of the draft guidance are highlighted below: 

A Type A meeting is necessary for a stalled product development program (at the behest of FDA) to proceed or to address an important safety issue.  Meetings of this type include dispute resolution meetings, meetings to discuss clinical holds, special protocol assessment resolution meetings, and post-action meetings requested within 3 months after an FDA regulatory action other than approval (i.e. complete response letter).  In the revised draft guidance, meetings requested within 30 days of FDA issuance of a refuse-to-file letter were also designated as Type A meetings.  For Type A meetings, FDA will aim to respond to a meeting request letter within 14 calendar days of receipt.  If a Type A meeting is granted, the meeting will be scheduled or a written responses only (WRO) communication will be sent within 30 calendar days from FDA receipt of the meeting request letter.  The requester must submit the Type A meeting package at the same time the meeting request letter is submitted and the FDA aims to provide preliminary responses no later than 2 calendar days prior to the scheduled meeting. 

Type B meetings include:  pre-investigational new drug application (pre-IND) meetings, pre-emergency use authorization meetings, pre-new drug application (pre-NDA)/pre-biologics license application (pre BLA) meetings, post-action meetings requested 3 or more months after an FDA regulatory action other than approval, meetings regarding risk evaluation and mitigation strategies of postmarketing requirements that occur outside the context of the review of a marketing application, and meetings held to discuss the overall development program for products granted breakthrough therapy designation status.  With the release of the revised draft guidance EOP1 and EOP2 (pre-phase 3) meetings no longer fall within this meeting category.  The FDA will aim to respond to requests for Type B meetings within 21 calendar days of receipt.  If the meeting is granted, the meeting will be scheduled or alternatively if the meeting is not granted WRO communication may be sent within 60 calendar days from FDA receipt of the meeting request.  The requester must submit the Type B meeting package no later than 30 days before the scheduled date of the meeting or WRO communication.  The FDA aims to provide preliminary responses no later than 2 calendar days prior to the scheduled meeting.

The revised draft guidance introduces a new category of meetings, Type B (EOP) meetings, which will include EOP1 meetings for certain products that will be considered for marketing approval under 21 CFR part 12, subpart E (Hearing Procedures), or 21 CFR part 314, subpart H (Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses; Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics), and EOP2 meetings.  The FDA will aim to respond to requests for Type B (EOP) meetings within 14 calendar days of receipt.  If granted, a meeting will be scheduled or WRO communication will be sent within 70 calendar days of FDA receipt of the request.  The requester must submit the Type B (EOP) meeting package no later than 50 days before the scheduled date of the meeting or WRO response time.  As compared with Type B meetings, the FDA will aim to respond quicker to a Type B (EOP) meeting request; however, there will be a longer timeframe for scheduling the meeting and meeting packages will need to be sent in sooner due to the time required for FDA to review the greater volume of information contained in these meeting packages.  The FDA aims to provide preliminary responses no later than 5 calendars prior to the meeting and the requester should respond to the FDA within 3 calendar days after receiving the preliminary responses stating whether the meeting is still needed and providing an updated agenda including any questions that still require discussion.

A Type C meeting is any meeting other than a Type A, Type B, or Type B (EOP) meeting regarding the development and review of a product.  The revised draft guidance expanded this definition to specifically include meetings to facilitate early consultations on the use of a biomarker as a new surrogate endpoint that has never been previously used as the primary basis for product approval in the proposed context of use.  The FDA will aim to respond to meeting request letters for a Type C meeting within 21 calendar days of receipt.  If granted, a meeting will be scheduled or WRO communication will be sent within 75 calendar days of FDA receipt of the meeting request letter.  The revised draft guidance also specifies that meeting packages for Type C meetings that are requested as early consultations on the use of a new surrogate endpoint must be submitted at the time the meeting request is submitted while all other Type C meeting packages must now be submitted no later than 47 days before the scheduled date of the meeting or WRO response time.  According to the revised draft guidance, the FDA now aims to provide preliminary responses 5 calendar days prior to a scheduled Type C meeting and requires the requester to respond within 3 calendar days after receipt of FDA’s preliminary responses.

A summary of this information is provided in the table below (Appendix   Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products).

Meeting Type FDA Response to Request FDA Reciept of Meeting Package FDA Preliminary Responses to Requester (if applicable) Requester Response to FDA Preliminary Response (if applicable) FDA Scheduled Meeting Date (days from receipt of request) FDA Meeting Minutes to Requester (if applicable)
A 14 days With meeting request No later than 2 days before meeting -- Within 30 days 30 days after meeting
B 21 days No later than 30 days before meeting No later than 2 days before meeting -- Within 60 days 30 days after meeting
B (EOP)* 14 days No later than 50 days before meeting** No later than 5 days before meeting No later than 3 days after receipt of preliminary responses Within 70 days 30 days after meeting
C 21 days No later than 47 days before meeting*** No later than 5 days before meeting No later than 3 days after receipt of preliminary responses Within 75 days 30 days after meeting

Not applicable to written response only.
* EOP = end of phase
** If the scheduled date of a Type B (EOP) meeting is earlier than 70 days from FDA receipt of the meeting request, the requester’s meeting package will be due no sooner than 6 calendar days after FDA response time for issuing the letter granting the meeting (see Table 1 in section VI.B., Meeting Granted).
*** If the scheduled date of a Type C meeting is earlier than 75 days from FDA receipt of the meeting request, the meeting package will be due no sooner than 7 calendar days after FDA response time for issuing the letter granting the meeting (see Table 1 in section VI.B., Meeting Granted). Note that for Type C meetings that are requested as early consultations on the use of a new surrogate endpoint to be used as the primary basis for product approval in a proposed context of use, the meeting package is due at the time of the meeting request.

Consistent with the draft guidance from 2015, each meeting type consists of 3 different formats:  face-to-face, teleconference/videoconference, and written response only (WRO) and the FDA will issue finalized meeting minutes within 30 calendar days after any type of meeting.  The revised guidance still notes that requesters should attempt to combine product development issues into the fewest possible meetings.  Information pertaining to the content of a meeting request letter and meeting package is also outlined in the revised draft guidance.  According to the Federal Register, comments should be submitted on this revised draft guidance by 29 March 2018.   

An additional related resource includes the recently finalized guidance outlining the“Best Practices for Communication Between IND Sponsors and FDA During Drug Development.” 

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10-Step Commercial Clinical Protocol Authoring Guide

Posted by Brook White on Thu, Aug 31, 2017 @ 01:57 PM
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Lauren Neighbours, PhD, RACLauren Neighbours, PhD, RAC, is a Research Scientist at Rho. She leads cross-functional project teams for clinical operations and regulatory submission programs. Lauren partners with early-, mid-, and late-stage companies to develop and refine strategic development plans, design and execute clinical studies, lead regulatory submissions, and provide support for regulatory authority meetings and other consulting needs. She has over ten years of scientific writing and editing experience and has served as a lead author on clinical and regulatory documents for product development programs across a range of therapeutic areas.

Devin Rosenthal, PhDDevin Rosenthal, PhD, RAC, works with companies at all stages of development to help them shape their product development programs. He has experience across the full drug development spectrum through his roles in small biotech, big pharma, and at Rho, with particular focus on oncology, CNS, gastrointestinal, and respiratory indications. In addition to pharmaceutical development, Devin is also involved in strategic alliance and business development activities at Rho.

Genna Kingon, PhDGenna Kingon, PhD, RAC, is a Research Scientist at Rho involved in regulatory strategy and submission management from pre-IND to post-approval.  She also serves as a lead regulatory author on multiple programs for submissions to FDA and to various international regulatory authorities.  In particular, Genna focuses on rare disease programs and expedited approval pathways. 

begin with the end in mindA protocol is the most important document in a clinical study as it is the foundation for subsequent operational, regulatory, and marketing objectives for the development program. 

 Developing a protocol is an extensive undertaking that requires a cross-functional team and consideration of the position and role of the study in the full product development program.  Before the protocol authoring process even begins, a variety of activities and decisions are necessary to establish a strategy for success.  The following steps provide concepts and considerations that are essential in formulating the details that will become the protocol synopsis and ultimately the clinical study protocol. 

Pre-Authoring

1.    Begin with the end in mind

our program team should first prepare an Integrated Product Development Plan (IPDP). This plan, which is largely based upon the desired final Target Product Profile (TPP) and product labeling, maps out all activities through marketing application submission and clearly outlines the purpose, position, and necessity of each study in the product development program. Without these documents, you run the risk of completing a study that fails to advance your product’s development or is markedly less valuable to development than it otherwise could be.

Among other things, the IPDP should contain the clinically meaningful endpoint(s) for your studies that will be acceptable to regulators and support the desired marketing claims for the product. Additionally, the IPDP should include an assessment of the actual and potential competitive products likely to be on the market at or near the time of product launch. This information will be essential for optimal study design and conduct, and will therefore improve the chances of ultimate product success. Cross-functional input and buy-in from all key internal and external stakeholders for each study, as well as on the full development plan, is a necessity.

2.    Design the study

clinical study designBefore you start thinking about the protocol study procedures and visit schedule, you need to understand your overall goals for the study, and how the data that are collected will not only support your product development strategy but ultimately move your program forward. For studies in the early phase of development, consider first outlining the study objectives, as well as the endpoints that specifically address those objectives in a measurable and meaningful way. The design of the study should then flow from those objectives and endpoints, making sure the technical and logistical aspects of the protocol maintain a focus on the end goals.

For all studies, consider developing the statistical analysis plan (SAP) before drafting the protocol. During SAP development, the study objectives and endpoints are comprehensively considered and designed, along with the specific analytical methods needed to optimally interpret the data. Choose a sample size that has sufficient statistical power to reliably detect outcomes and differences of interest and that meaningfully contributes to accumulation of an adequate safety database for your product, but is also as practical as possible to enable successful study completion. Then, explore study design options with the protocol objective(s), SAP, and the TPP in mind.

In designing your study, take the following into account:

  1. Map out how key study measures will be assessed, with what frequency, and in what kind of study population.  Properly defining the study population is essential, particularly to ensure that the inclusion and exclusion criteria appropriately select for the eventual target population, as well as for optimal assessment of safety and efficacy in that population. 
  2. Be sure that existing animal toxicology data are adequate to support any proposed duration of dosing, dose levels, and specific subject eligibility criteria.
  3. Be mindful of manufacturing capacity and schedules for study drug to ensure that your study is feasible given the cost of goods and timelines for manufacturing.  You may have to adjust the dosing duration, dosage, number of dose levels, or your study timeline to accommodate manufacturing limitations.  Even after your drug is manufactured, you may want or need to develop specialized packaging such as blister packaging or cold-chain logistics to help ensure study success.
  4. Remember that the more complex the study design (e.g., number of arms, number of objectives and endpoints, number or complexity of assessments), the greater the chances for errors, omissions, data quality issues, and unexpected complications during study execution; and, therefore, the greater the chance for study failure.  Study design should be laser focused on what is required to produce only the information necessary for product labeling and/or to progress the compound to the next stage of development.  For this reason, it is also important to avoid the common temptation of adding “nice-to-have” but inessential study components during the course of protocol development. 

3.  Define technical details

Establish or obtain an International Conference on Harmonisation (ICH)-compliant protocol template and develop and maintain a style guide and/or list of writing conventions to ensure consistency and clarity within and between study documents.  Establish the appropriate reviewing processes, and identify cross-functional reviewers (editorial, regulatory, clinical, statistical, data management, medical, product safety, senior management, etc.).  Record all key decisions and their rationale throughout the development and writing process.  Failure to do so may result in frequently having to revisit issues, causing unnecessary delays and changes in the protocol or development plan.

4.  Draft the synopsis

Generate the study schedule of events, and draft the synopsis.  The synopsis should be no more than 10 pages total.  Obtain feedback from cross functional subject matter experts, senior leadership from the sponsor/contract research organization (CRO), and potential clinical investigators and study site staff.  Revise and finalize the synopsis:  this is the foundation for the clinical study protocol.  

Protocol

5.  Define operational details

Consider essential operational logistics such as laboratory test results required to enroll and/or randomize subjects (e.g., will this require local labs as opposed to a central lab?), total blood volume drawn, equipment and space necessary for subject evaluation, availability of specialist(s) for nonstandard assessments, storage and shipping requirements for clinical specimens and investigational product, and scheduling limitations/conflicts for study visits.  Consult both sponsor and CRO operations staff and study sites as necessary to determine the feasibility of the proposed operational plan.  

6.  Minimize the potential for amendments

simplify the protocol where possibleConsider what qualifies for inclusion in the protocol; detailed information that is not directly relevant to study conduct is usually better suited for operations manuals, which can be more easily updated throughout the study.  Avoid redundancy within the protocol; state everything once.  Use the synopsis as a tool to establish the foundation of the protocol.  At the completion of protocol development, the synopsis should be reviewed to ensure it accurately reflects the content of the final protocol (if it is intended to be appended to the protocol or used separately as an internal reference tool).  Continuously revising the synopsis while the protocol is being written is unnecessary and discouraged as this invariably leads to errors in one document or the other, as well as in the resulting study.  Whether or not a synopsis is included in the final protocol itself is often a matter of sponsor preference. 

7.  Draft the protocol

Prepare the protocol draft by expanding on the detail in the synopsis regarding the investigational plan, study schedule, analysis plan, safety monitoring, and the other outlined provisions.  Much of the protocol should be derived from template language, which generally does not change from protocol to protocol, but rather, only changes periodically following revised regulatory requirements or other administrative preferences.  Obtain additional review from cross-functional subject matter experts (which may include patient advocacy groups, as applicable), the sponsor and/or CRO personnel, and select study investigators.

Download: Protocol Template

Concurrent and/or Post-Protocol

8.  Draft the informed consent form (ICF)

Using an established and compliant informed consent form (ICF) template, draft the ICF with finalized protocol information at the appropriate reading level for the intended study subjects, which is rarely greater than about an eighth-grade level.  Obtain cross-functional subject matter expert and sponsor/CRO/site feedback.  Revise and finalize the form, which may require site- and institutional review board (IRB)-specific information or even site/IRB specific template language.  While the consent must include all required regulatory elements, strive to make the consent form as short as possible and without repetition.  A consent form that is overly complicated or too long to be easily read and understood fails in its purpose.

9.  Design case report forms (CRFs)

case report forms (CRFs)Capture data efficiently (fewer queries) with appropriate and reasonable CRF pages.  Be considerate of open-ended text boxes versus check boxes:  while an open-ended text box is preferable for describing unexpected, non-categorical events, check boxes are better for categorical items (e.g., ethnicity) to reduce the need for queries and to facilitate downstream data analysis.  The CRF should undergo interdisciplinary review by representatives from key functional areas (i.e., data management, biostatistics, programming, clinical operations, regulatory, safety, medical affairs) prior to finalization. 

10.  Design and compile operations manuals

The clinical sites will reference operations manuals for additional study information that is not specified in detail in the protocol (e.g., pharmacokinetic sampling procedures, shipping information, tissue collection procedures, investigational product preparation/dispensation, study contact information, etc.).  Use the manuals as an easily accessible reference for site study staff and a repository for information that has the potential to change during the study (e.g., shipping addresses if personnel/vendors are likely to change).

Download: Protocol Template