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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 For example, the draft guidance notes that sponsors should have medical monitors with appropriate training and experience in the conduct of clinical trials and the indications under study,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

 

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.

Download: Marketing Application Planning Tool

Key Take-aways from ACRP 2017

Posted by Brook White on Fri, May 05, 2017 @ 11:15 AM
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key take aways from ACRPThis week I attended the 2017 ACRP Annual Meeting in Seattle.  Here are some of the key trends, themes, and ideas that I took away.  There were obviously far more sessions than any one person could attend, so I’m sure there are pieces I missed.  If you attended, please feel free to add your thoughts to the comments below.

Core Competency Framework for Clinical Study Monitoring

framework for clinical study monitoringOne of the biggest announcements of the conference was that the Workforce Development Task Force and Steering Committee released a core competency framework for clinical study monitoring.  The goal of the framework is to standardize professional expectations for individuals involved in clinical study monitoring.  The framework is intended to define competency requirements for individuals involved in study monitoring regardless of experience level across eight domains—clinical operations/GCPs, communication and teamwork, data management and informatics, ethical and participant safety concerns, leadership and professionalism, medicines development and regulation, scientific concepts and research design, and study and site management. The core competency framework can be downloaded here.

ACRP Announces New Certification Program

certified professionalACRP announced a new certification program, ACRP-CP (certified professional).  The new certification provides a non-role specific alternative to the existing role specific Certified Clinical Research Associate (CCRA), Certified Clinical Research Coordinator (CCRC), and Certified Principal Investigator (CPI) certifications.  The new credential seeks to formally recognize individuals with the skills, knowledge, and abilities to perform ethical and responsible clinical research regardless of their specific role.  The first certification exam will be held this Fall.

Transparency and Flexibility from FDA

regulatory transparencyThe first session on Saturday was a panel discussion with four speakers from FDA—three from the Center of Drug Evaluation and Research (CDER) Office of Scientific Investigations (OSI), and one from CDER Office of Integrity and Surveillance. As I commented following ACRP and DIA last year, FDA seems to be making a concerted effort to be accessible, transparent, and flexible in communicating with professionals involved in research. As a matter of fact, one of their stated strategic goals was stakeholder engagement (the others were user fee requirements, responsible stewardship, global context, and subject rights, safety, and welfare). They also stated that in places where existing guidance and precedence doesn’t exist and is needed to move research forward, drug developers should come to them with questions rather than waiting for formal guidance. In addition to the panel discussion, the three speakers who attended in person stuck around and held office hours Saturday and Sunday to talk to conference participants.

The panel addressed several questions that related to themes seen more broadly at the conference.

State of the Industry

Day 2 opened with a panel discussion on the state of the industry featuring ACRP President Jim Kremidas, Ken Getz from Tufts University Center for the Study of Drug Development (CSDD), Elisa Cascade, President of Data Solutions, Leanne Madre Director of Strategy for the Clinical Trials Transformation Initiative (CTTI) at Duke University, and ACRP’s Workforce Innovation Officer, Terri Hinkley.  The panel focused their discussion on four broad forces impacting clinical trials:

  • Consolidation
  • Datafication
  • Integration
  • Uberization

Organizations involved in clinical trials are consolidating across the continuum. We are seeing both consolidation for economies of scale—CRO mergers and acquisitions, sites fusing into site networks—and vertical consolidation where organizations are increasing their capabilities—CROs buying site networks and central labs. It remains to be seen how this will impact clinical trials as a whole.

Datafication is the increased ability to gather and access ever increasing amounts of both structured and unstructured data that can be used in clinical research. The average phase III study now collected nearly 1 million data points. Additionally, we are seeing more data that is collected to drive payer and prescriber behavior rather than just to demonstrate safety and efficacy.

Integration refers to the efforts to better connect people, processes and technology. There are a number of national level initiatives to improve clinical research like CTTI, TransCelerate, and MDIC, a device and diagnostic initiative. These organizations have potential to move some agreed upon concepts from idea to reality. For example, both the NIH and the 21st Century Cures Act call for use of central IRBs, and CTTI is working on tools that can help make that happen. When it comes to technology, the perception is that the industry is suffering from “death by pilot.” People and organizations are willing to try lots of new technology, but consistent industry wide adoption is incredibly slow and lacking in standardization. Even EDC, which is hardly new or innovative at this point, is only used by 50% of studies globally. Common complaints and barriers include lack of consolidated platforms and the need to use different software and different login information for each study.

Uberization is moving research into healthcare in a way that works best for patients. There are greater pressures than ever to make research patient friendly rather than convenient for sites, PIs, CROs, and sponsors. Without patients, studies won’t happen. In this talk as well as others, there is a sense that patient centric practices aren’t just the right thing to do, they are necessary to succeed in research.

Finally, the panel identified key drivers for change over the next 3-5 years:

  • Collaboration: Industry and CROs working together allow for standardization and process improvement.
  • Regulatory willingness to try new things.
  • The internet of things—devices in our lives provide access to information in new and objective ways.
  • Technology that is easy enough to use that training isn’t necessary.

Innovating Clinical Trials with Mobile Technology

mobile technology for clinical trialsDay 3 featured a panel discussion on the CTTI mobile technology initiative.  The initiative contains four working groups addressing:

  • Mobile devices
  • Novel endpoints
  • Stakeholder perceptions
  • Legal and regulatory issues

The goal is to provide evidence-based recommendations that allow an increased number of clinical trials to leverage mobile technologies.

One question they addressed upfront was the benefit of using mobile given the additional effort needed, and they provided four key answers:

  • Potential reduction of burden on trial participants
  • Increased patient access to clinical trials
  • Availability of objective data
  • Ubiquity of devices

The initiative has focused on studies conducted in the US, although they recognize it is a global issue. The stakeholder perception group is addressing concerns about security as well as concerns about losing the time and attention of the doctor providing care. The novel endpoints group is looking at new endpoints that are now possible to assess as well as existing endpoints that can be assessed more easily or more accurately than is possible with non-mobile technologies. The mobile devices group is looking at devices that can address existing challenges, data attribution concerns, and the identification of the difference between real needs to address research questions versus data fishing expeditions. The legal and regulatory group has its hands full with a variety of issues—understanding FDA’s willingness to accept mobile technologies, addressing privacy and confidentiality concerns, telemedicine challenges, dealing with IRBs, shipping issues, and reimbursement.

Finally, people were invited to engage in the process by signing up for updates or to participating in evidence gathering (ctti@mc.duke.edu).

eHRs and Study Oversight

A significant concern expressed by auditors and monitors alike in a number of sessions is that site and institutions implementation of eHR systems do not provide adequate mechanisms for monitors and auditors to provide oversight.  In some cases they are being provided with copies or printouts that are illegible rather than provided with direct access to eHR systems.  In other cases, they are provided with access to eHR systems, but important information is sequestered.  A common complaint is that sensitive records like those associated with mental illness, sexually transmitted infections, and substance abuse is are not being made available even when those records are relevant to the research and may reflect AEs.  In one example, it came to light that a subject had attempted suicide while on an investigational product, but it was not initially reported as an AE and the study monitor was not allowed access to the record.  With the increased use of eHRs in healthcare settings, this is not likely an issue to go away soon.

ICH E6 R2

Not surprisingly, many if not most sessions touched on the impact of the ICH E6 revisions and their impact to studies.  Additionally, there was a two part session held specifically to review the revisions and discuss their impact.  This is an extensive topic that is well discussed elsewhere, so I won’t go into detail here. 

Importance of Conducting Ethical Research

While this isn’t new, ACRP continues to press the importance of conducting clinical research in ethical ways and expecting professionals involved in research to understand what that means.  There were a number of excellent sessions on research misconduct and the relationship to public trust, ethical considerations in pediatric research, and recognizing vulnerable patients and patient populations.

Business Intelligence and Study Management

As the global volume of available data sources increases exponentially, those in clinical research are becoming more aware of the benefits of transforming these raw data sources into useful information for analysis purposes. The ability to effectively utilize the data we currently have depends on the thoughtful construction of metrics and key performance indicators (KPIs). The simple establishment of these types of measures must develop an even balance; a study can have too many metrics (which confuse the purpose), too few metrics (which offer weak benefit and minimal impact), or a focus that is too broad where one area grows strong at the expense of another. Other common pitfalls are underestimations of the time and effort required to combine various data sources, imbalances between metrics and action, and metrics that are developed for the sake of metrics. The development and use of these metrics and KPIs requires a cycle of continuous improvement: High-impact metrics must be identified and developed, accurate data gathered, and the lessons learned converted to actionable strategies and reassessed continually to correctly estimate our return on investment.

Thanks to Derek Lawrence for contributing to this article.

Big Data: The New Bacon

Posted by Brook White on Wed, Nov 16, 2016 @ 04:10 PM
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Dr. David Hall, Senior Research ScientistDavid Hall is a bioinformatician with an expertise in the development of algorithms, software tools, and data systems for the management and analysis of large biological data sets for biotechnology and biomedical research applications. He joined Rho in June, 2014 and is currently overseeing capabilities development in the areas of bioinformatics and big biomedical data. He holds a B.S. in Computer Science from Wake Forest University and a Ph.D. in Genetics with an emphasis in Computational Biology from the University of Georgia.

big data is the new baconData is the new bacon as the saying goes. And Big Data is all the rage as people in the business world realize that you can make a lot of money by finding patterns in data that allow you to target marketing to the most likely buyers. Big Data and a type of artificial intelligence called machine learning are closely connected. Machine learning involves teaching a computer to make predictions by training it to find and exploit patterns in Big Data. Whenever you see a computer make predictions—from predicting how much a home is worth to predicting the best time to buy an airline ticket to predicting which movies you will like—Big Data and machine learning are probably behind it.

However, Big Data and machine learning are nothing new to people in the sciences. We have been collecting big datasets and looking for patterns for decades. Most people in the biomedical sciences consider the Big Data era starting in the early to mid-1990s as various genome sequencing projects ramped up. The human genome project wrapped up in 2003, took more than 10 years, and cost somewhere north of $500 million. And that was to sequence just one genome. A few years later, the 1000 Genome Project started, whose goal was to characterize genetic differences across 1000 diverse individuals so that we can predict who is susceptible to various diseases among other things. This effort was partially successful, but we learned that 1000 genomes is not enough.

cost of human genome sequencingThe cost to sequence a human genome has fallen to around $1,000. So the ambition and scale of big biomedical data has increased proportionately. Researchers in the UK are undertaking a project to sequence the genomes of 100K individuals. In the US, the Precision Medicine Initiative will sequence 1 million individuals. Combining this data with detailed clinical and health data will allow machine learning and other techniques to more accurately predict a wider range of disease susceptibilities and responses to treatments. Private companies are undertaking their own big genomic projects and are even sequencing the “microbiomes” of research participants to see what role good and bad microbes play in health.

Like Moore’s law that predicted the vast increasing in computing power, the amount of biomedical data we can collect is on a similar trajectory. Genomics data combined with electronic medical records combined with data from wearables and mobile apps combined with environmental data will one day shroud each individual in a data cloud. In the not too distant future, maybe medicine will involve feeding a patient’s data cloud to an artificial intelligence that has learned to make diagnoses and recommendations by looking through millions of other personal data clouds. It seems hard to conceive, but this is the trajectory of precision medicine. Technology has a way of sneaking up on us and the pace of change keeps getting faster. Note that the management and analysis of all of this data will be very hard. I’ll cover that in a future post.

View "Visualizing Multivariate Data" Video

Scientists Search for Answers as Antibiotics become Obsolete

Posted by Brook White on Thu, Aug 18, 2016 @ 01:41 PM
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Carrie Furr, PhD, RACCarrie Furr, PhD, RAC, is a Senior Director Operations at Rho. Day-to-day, Carrie supports pharmaceutical sponsors of clinical trials, leading an integrated product development program consisting of clinical, preclinical, chemistry, manufacturing and controls, and regulatory components. Before diving into the clinical trials industry, Carrie spent 7 years earning her PhD in biochemistry, bacteriology and bacteriophage biology at Texas A&M University. A biologist by training, Carrie’s dissertation and doctoral research focused on how a bacteriophage (phage) protein causes bacteria to die. In theory, phage proteins can be used in phage therapy to combat any bacteria-based disease. 

As anyone who has ever had a bacterial infection or seen an end-of-the-world survival movie knows, antibiotics are an important tool in a doctor’s arsenal. Since the discovery of penicillin in 1928, antibiotics have been extremely effective at treating and preventing a variety of infections. But imagine life without them – doctors unable to prevent infections after surgery, your child’s minor cut might morph into a major infection, and there wouldn’t even be a treatment for pink eye.

With the increasingly popular use of antibiotics, however, microbes have mutated and learned to resist the drugs. Penicillin was once extremely effective against most strains of bacteria, but now it is used far less frequently as many strains have built up resistance. In many cases antibiotics are becoming obsolete.

What can be done? Without antibiotics, a huge range of diseases -- from pneumonia to strep throat to syphilis – would become much more difficult, if not impossible, to treat. While there are a few things you can do to help prevent antibiotics from further increasing resistance – for example, taking all prescribed antibiotics even if you feel better or only taking antibiotics when you truly have an infection – it isn’t enough. Scientists need to work on other solutions.

phage, bacteriophageBacteriophages, or “phages” for short, may be able to help. Certain phage proteins cause bacteria to die. Researchers are working to determine if these proteins or whole phages can be safely converted into therapies to combat bacteria-based diseases. Developing an alternative treatment to antibiotics could have huge implications on the treatment of bacterial infections around the world. Additionally, phage therapy holds the promise of providing a dynamic solution to the dynamic problem of antibiotic resistance.

While academics and pharmaceutical companies work on the research, people like me are working on smoothing the road to U.S. Food and Drug Administration (FDA) approval for these novel therapies. As a postdoctoral researcher, I focused on how bacteriophages can kill certain bacteria. As a senior regulatory scientist, I work on the practical steps required to bring pharmaceutical products, including phage therapy, into the market to treat patients. Currently, the path to develop phage therapy through to regulatory approval is unclear.

In the face of antibiotic resistance in the U.S. and around the world, it is important to understand our alternatives and what must be done to advance alternative treatments.

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