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Update from the top: FDA’s Office of New Drugs ongoing reorganization process

Posted by Karl Whitney on Thu, Jan 02, 2020 @ 11:00 AM
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karlKarl Whitney, PhD, RAC, 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.

Rho representatives joined regulators, industry scientists, and numerous patient-advocacy groups at CBI's Rare Disease Clinical Development & Access conference in Washington 03-04DEC 2019. During an opening plenary session, FDA's Office of New Drugs (OND) director Dr. Peter Stein shared comments and took questions from the audience. Participants asked a number of questions that indicate a high degree of interest in (and, perhaps, some anxiety about) OND's ongoing reorganization in general and as it might affect specific current projects at the IND or NDA review stage. This reorganization was announced earlier in 2019 and will, among other things, increase the number of offices overseeing review divisions from 6 to 8, and split and/or redesign review divisions to increase the number of divisions from 19 to 27. The reorganization is being implemented in four phases, with the last set to complete by February 2020. Dr. Stein certainly attempted to address some of the audience's concerns. His key message: the ongoing reorganization is intended to improve review processes while ensuring continuity for individual projects. In short, FDA doesn't want to fix what ain't broke.

Instead, the overall goals are to establish more therapeutically aligned, integrated review teams that take an interdisciplinary and 'problem-focused' approach to reviews; and to modernize and standardize review processes across divisions. In the process, he and hOptimization - Business Concept. Golden Compass Needle on a Black Field Pointing to the Word Optimization. 3D Render.is team are taking great care to ensure OND operates smoothly, and that review teams have a re-energized scientific focus for their work.

On the former, he hopes the reorganization will make for more sensible Division groupings. Some large divisions such as Neurology or GI/inborn errors are being split up so that Division Leadership can spend more time on the science and be more externally facing  (eg, at conferences). Individual review teams are being kept together as much as possible when these new divisional groupings are being designed. Further, he has instructed Division heads overall to avoid revisiting prior agreements made between the sponsor and the review team if the team has moved divisions. He believes strongly that it's in nobody's interest to upend established agreements, though he reminded the audience that of course, FDA reserves the right to update its positions as new data accrue. So, sponsor caveat emptor.

On the latter, OND is trying to enhance reviewer consistency and throughput by using a new review template and improved processes that support efficient, integrated reviews of submissions from IND through to approval/post-approval. In addition, a new non-review office called Office of New Drug Policy has been established to support review teams when novel Orange Business Processes Button on Computer Keyboard. Internet Concept.issues come up that lack clear guiding precedent, so that review teams across the OND approach novel issues with greater consistency. Another new cross-cutting office of interest to conference attendees is the planned Division of Rare Disease and Medical Genetics within the new Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine. This group will not have direct review responsibilities but rather will offer 'consultative support' to help review teams properly exercise 'flexibility' in product development programs for example in terms of expected safety database size, a topic that commonly arises, naturally, with rare disease development programs. These rare-disease sponsor projects will still be overseen by the Division that makes the most sense from a therapeutic area - for example, Division of Anti-infectives. The new Division of Rare Disease and Medical Genetics group will also have a mandate to engage outside FDA with patient groups, other regulatory bodies, academia, and even Advisory Committees to ensure they understand realities for rare disease product development. One can only speculate as to why these new responsibilities were not assigned to the longstanding Office of Orphan Product Development.

Overall, the audience took a wait-and-see approach insofar as the reorganization is ongoing and the chips haven't fallen yet. Time will tell if the major goals of the reorganization are achieved by this structure, but Dr. Stein certainly made his best case for the various rationales for the temporary upheaval. Maybe spring cleaning came a bit early to the OND this year....

 

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

 

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

Age Diversity in Clinical Trials: Addressing the Unmet Need

Posted by Brook White on Tue, Jul 10, 2018 @ 09:23 AM
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Ryan2Ryan Bailey, MA is a Senior Clinical Researcher at Rho.  He has over 10 years of experience conducting multicenter asthma research studies, including the Inner City Asthma Consortium (ICAC) and the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) project. Ryan also coordinates Rho’s Center for Applied Data Visualization, which develops novel data visualizations and statistical graphics for use in clinical trials.

elderly patient with nurseIn a recent New York Times article, Paula Span raises the concern that elderly subjects are frequently omitted from clinical trials.  Consequently, physicians know very little about how a given treatment may affect their older patients.  Is a medication effective for the elderly?  Is it safe?  Without data, how is a physician to know?  

Span’s article is timely and aligns well with similar industry trends toward increased patient centricity and trial diversity.  Yet, expanding trials to include older patients poses a challenge for research teams because it brings two tenets of quality research into conflict with one another – representative study populations and patient safety.  

The fundamental assumption of clinical trials research is that we can take data from a relatively small, representative selection of subjects and generalize the results to the larger patient population.  If our sample is too constrained or poorly selected, we hinder the broad applicability of our results.  This is not merely a statistical concern, but an ethical one.  Unfortunately, our industry has long struggled with underrepresentation of important demographic groups, especially women, racial and ethnic minorities, and the elderly. 

At the same time, researchers are keenly concerned about protecting subject safety in trials.  Good Clinical Practice is explicit on this point: 

2.3 The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

Such guidance has engendered broad reluctance to conduct trials in what we deem “vulnerable populations,” namely children, pregnant, and the elderly.  The risk of doing more harm than good in these patient groups often leads us to play it safe and exclude these populations from trials.  Span, however, provides an astute counterpoint: expecting providers to prescribe a medication to a group of patients who were not included in the original research is equally irresponsible.  

No case illuminates the challenging catch-22 we face like the awful thalidomide debacle of the 1950s-60s.  Thalidomide, which was widely regarded as safe, was prescribed off-label for pregnant women to treat morning sickness.  Tragically, the drug was later linked to severe birth defects and banned for expecting mothers.

On one hand, the physicians prescribing thalidomide did so based on limited knowledge of the drug’s safety in pregnant women.  Had a trial had been conducted that demonstrated the risk to children, they would clearly know not to prescribe it to expecting mothers.  Yet, the very risk of such dangerous complications is why such trials are not conducted in vulnerable populations in the first place.  Risks for the elderly are different than for pregnant women, but the principal of protecting sensitive populations is the same.  

Span notes that even in studies that don’t have an explicit age cap, many protocols effectively bar elderly participants via strict exclusion criteria that prevent participation by people with disorders, disabilities, limited life expectancy, cognitive impairment, or those in nursing homes.  It must be stated, however, that the reason for such conditions is not to be obstinately exclusive but to reduce confounding variables and minimize risks to vulnerable patients.  In most cases, it would be patently unethical to conduct research on someone with cognitive impairment or in a nursing home where they may be unable to give adequate informed consent, or they may feel coerced to participate in order to continue receiving care.

So, how do we negotiate this apparent impasse?  Span offers a few general suggestions for increased inclusion, including restructuring studies and authorizing the FDA to require and incentivize the inclusion of older adults.  Changing the laws and enforcement can certainly drive change, but what can we do in the near term, short of legislative intervention?  

elderlycoupleA few quick suggestions:

  1. Reconsider age limits and avoid an all-or-none mentality to enrolling geriatric subjects.  The mindset that older adults are, as a whole, too vulnerable to enroll is usually an overreach.  In most cases, age limits are imposed as a convenience for the study, not a necessity.  Instead, consider evaluating eligibility on a subject-by-subject basis, which will still allow exclusion of patients deemed too frail, risky, or comorbid for the trial.  
  2. Actively recruit older subjects. The lack of geriatric patients in our trials is a result of many years of both passively and actively excluding them, so effort is needed to reverse these trends.  Beyond recruitment for an individual trial, researchers and providers should seek to educate older adults about clinical research.  Many elderly patients may be research-naïve – unfamiliar with clinical trials and how to participate, or unaware of available trials in their area.  
  3. Learn from other efforts to recruit marginalized populations.  As we’ve shared previously, improving trial diversity starts with an effort to thoroughly understand your patient population and their needs, and reduce obstacles to their participation.  
  4. Engage patient advocacy groups that focus on elderly patients.  Ask how trials can be better designed to meet their needs and include them.  Partner with these groups to aid in information sharing and outreach.
  5. Learn what is already expected from agencies like the FDA and NIH when it comes to inclusivity. 
    1. Span alludes to a recent NIH policy revision (stemming from the 21st Century Cures Act) that will require new NIH grantees to have a plan for including children and older adults in their research.
    2. In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) required the FDA to create an action plan to improve data quality and completeness for demographic subgroups (sex, age, race, and ethnicity) in applications for medical products. 
  6. Design studies to examine effectiveness (demonstrating that a treatment produces desired results in ‘real world’ circumstances) not just efficacy (demonstrating that a treatment produces desired results in ideal conditions).  This is probably the most labor intensive because it requires additional investment beyond the typical Phase III randomized controlled clinical trial.  Yet, it is becoming more common to explore effectiveness through pragmatic trials, Phase IV studies, and post-market surveillance.   

“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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Could Your Drug Development Program Benefit from an NDA/BLA/PMA Gap Analysis?

Posted by Brook White on Wed, Aug 23, 2017 @ 09:37 AM
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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.  

Jack Modell, MD--Vice President and Senior Medical OfficerJack Modell, MD, Vice President and Senior Medical Officer, is a board-certified psychiatrist with 30 years of experience in clinical research, teaching, and patient care including 10 years of experience in clinical drug development (phases 2 through 4) and successful NDA filings. Dr. Modell is a key opinion leader nationally known for leading the first successful development of preventative pharmacotherapy for the depressive episodes of seasonal affective disorder.

scott-burian.jpgScott Burian, PhD, Senior Research Scientist, has contributed to the development of a diverse range of small molecule, biologic, and nanoparticle-based products.  He has participated in numerous FDA interactions, including pre-IND meetings, Type A meetings, and Advisory Committee meetings. He is fully-versed in eCTD format and has authored a variety of CMC submissions, including numerous pre-IND meeting packages, INDs, NDAs, and IMPDs.

bridging the gap between clinical data and NDA submissionHere at Rho, we’ve helped many companies with their marketing application submissions. In fact, in the past six years, we’ve been a key service provider on 14 submissions, provided biostatistics support for 30 submissions, and prepared over 20 Integrated Summary of Safety (ISS) and Integrated Summary of Efficacy (ISE) SAPs. Over the course of working on these submissions, one common hurdle we see is that Sponsor companies often enter this stage without a strong understanding of what data they have and how that maps to a viable approval pathway.

Whether you plan to file a new drug application (NDA), a biologics license application (BLA), or a premarket approval application (PMA) with the FDA or a marketing authorization application (MAA) with the European Medicines Agency, you’ll need an in depth understanding of how the data you have from your clinical studies, nonclinical studies, and Chemistry, Manufacturing and Controls (CMC) / Quality development map to the requirements of the application. These requirements can be specific to the therapeutic area or regulatory authority, and are continually changing as science advances.

Discovering you don’t have all the data you need as you begin preparing your marketing application can lead to costly time delays. What can be done? We recommend undertaking a gap analysis following proof-of-concept in Phase II. This timing allows you to design your adequate and well-controlled studies to attain all necessary clinical data. Performing the gap analysis at this stage of development will also provide enough time to conduct additional nonclinical studies or CMC development that may be needed to support the application.
You need a cross-functional team of medical, regulatory, clinical, statistical, CMC, and toxicology experts with experience getting a product to market, ideally in the therapeutic area of interest. Many small to mid-size companies don’t have all of this expertise in-house, so the team will need to bring in outside support in the form of consultants or a contract research organization (CRO) that has this expertise.

A gap analysis starts with a detailed look at the existing data and regulatory communications. What is the format of the data? Anything you plan to submit will need to be in CDISC format, so if you need data from legacy studies, the data must be converted to CDISC format if the study was initiated after December 2016. Next, look at the label claims you plan to make. Do you have (or have a plan to collect) all the data needed to support those claims? This can be difficult to determine.

mapping clinical dataOnce you’ve determined the data you have and the data you’ll need, create a map that clearly identifies the deficiencies in your database. You may find that there are very few gaps and the data you’ve collected and will collect in your pivotal studies will adequately support your marketing application. You may also realize that you don’t need all of the data from your legacy studies, which can save you some time and money in CDISC conversion costs. Conversely, you may identify significant gaps in your database that require additional studies. That is still a good outcome because by performing the gap analysis you have clearly identified what needs to be completed and you will have sufficient time to gather the additional data. This could mean just completing your Phase 3 studies, or performing additional clinical (e.g. food effect studies) or nonclinical studies, or CMC development work, thus ensuring that upon completion of the Phase III studies, you will have a clear path to your marketing application submission.

So, is the additional time and expense of conducting a gap analysis worth it? Rho believes that the answer is most definitely, yes. However, we typically recommend waiting until proof-of concept has been demonstrated to conduct this analysis. At that point, you should have convinced yourself that you have a viable product and have a general idea of its characteristics and potential value to patients. An experienced team of medical, nonclinical, CMC, regulatory, and statistical experts can conduct a gap analysis relatively quickly and for a relatively limited cost. When compared to a significant delay between the end of Phase 3 and submission or an unsuccessful marketing application submission, it is almost certainly worth it.

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