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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.

Download: Marketing Application Planning Tool

FDA Guidance on Non-Inferiority Clinical Trials to Establish Effectiveness

Posted by Brook White on Thu, Apr 20, 2017 @ 11:42 AM
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Heather Kopetskie, Senior BiostatisticianHeather Kopetskie, MS, is a Senior Biostatistician at Rho. She has over 10 years of experience in statistical planning, analysis, and reporting for Phase 1, 2 and 3 clinical trials and observational studies. Her research experience includes over 8 years focusing on solid organ and cell transplantation through work on the Immune Tolerance Network (ITN) and Clinical Trials in Organ Transplantation (CTOT) project.  In addition, Heather serves as Rho’s biostatistics operational service leader, an internal expert sharing biostatistical industry trends, best practices, processes and training.

In November 2016, the FDA released final guidance  on Non-Inferiority Clinical Trials to Establish Effectiveness providing researchers guidance on when to use non-inferiority trials to demonstrate effectiveness along with how to choose the non-inferiority margin, test the non-inferiority hypothesis, and provide interpretable results. The guidance does not provide recommendations for how to evaluate the safety of a drug using a non-inferiority trial design. This article provides background on a non-inferiority trial design along with assumptions and advantages and disadvantages of the trial design.

Background

A non-inferiority trial is used to demonstrate a test drug is not clinically worse than an active treatment (active control) by more than a pre-specified margin (non-inferiority margin). There is no placebo arm in non-inferiority trials. A non-inferiority trial design is chosen when using a placebo arm would not be ethical because an available treatment provides an important benefit, especially for irreversible conditions (e.g. death). Without a placebo arm to compare either the test or active control against it is important to determine that the active control had its expected effect in the non-inferiority trial. If the active control had no effect in the non-inferiority trial it would not provide evidence that the test drug was effective.
The table below compares superiority with non-inferiority trials with respect to the objective and hypotheses. The effect of the test drug is ‘T’ and the effect of the active control is ‘C’. The difference tested during analyses is C – T.

  Superiority Trial Non-inferiority Trial
Objective To determine if one intervention is superior to another To determine if a test drug is not inferior to an active control intervention, by a preset margin
Null Hypothesis No difference between the two interventions The test drug (T) is inferior to the active control (C) by some margin (M) or more (C – T >= M).
Alternative Hypothesis One intervention is superior to the other The test drug (T) is inferior to the active control (C) by less than M (C-T < M)

 

Selecting a non-inferiority margin in a trial is challenging but also critical to a successful trial. The largest possible choice for the non-inferiority margin is the entire known effect of the active control compared to placebo, called M1. However, doing this, would lead to a finding that the test drug has an effect greater than 0. More generally, the non-inferiority margin is set to some portion of M1, called M¬2, to preserve some effect of the control drug, based on clinical judgment. For example, if a superiority trial of the active control demonstrated to be 15% better than placebo, a clinician may set the non-inferiority margin to be 9% (M1=15%, M2=9%). This would be 6% worse than the active treatment, but still 9% better than placebo.

Multiple results are possible in a non-inferiority trial as explained in the graphic below. The point estimate is indicated by the square and is the measure of C – T; the bars represent a 95% confidence interval; and ∆ is the non-inferiority margin.

non-inferiority drug trial, interpretation of results

  1. Point estimate favors test drug and both superiority and non-inferiority are demonstrated.
  2. Point estimate is 0 suggesting equal effect of active control and active treatment. The upper bound of the 95% confidence interval is below the non-inferiority margin so non-inferiority is demonstrated.
  3. The point estimate favors the active control. The upper bound of the 95% confidence interval is less than the non-inferiority margin, demonstrating non-inferiority. However, the point estimate is above zero indicating that active treatment is not as good as the active control (C – T > 0), even while meeting the non-inferiority standard.
  4. Point estimate is 0 suggesting equal effect, but the upper bound of the 95% confidence interval is greater than the non-inferiority margin so non-inferiority is not demonstrated.
  5. Point estimate favors the active control and the entire confidence interval is above the non-inferiority margin so inferiority is demonstrated.

Non-inferiority Margin

The selection of the non-inferiority margin is critical in designing a non-inferiority trial and the majority of the FDA guidance focuses on this. The non-inferiority margin is selected by reviewing historical trials of the active control. The active control must be a well-established intervention with at least one superiority trial establishing benefit over placebo. If approval of the active control was based on a single study (not unusual in the setting of risk reduction of major events such as death, stroke, and heart attack), changes in practice should be evaluated. Using the lower bound of the 95% confidence interval provides a conservative estimate of the active control effect. If multiple historical trials exist one of the assumptions of the non-inferiority trial is consistency of the effect between the historical studies and the non-inferiority trial. Therefore, if consistency isn’t present between the historical studies this can lead to problems in estimating the active control effect. Inconsistency can also sometimes lead researchers away from performing a non-inferiority trial, especially if a historical trial did not demonstrate an effect. In situations with multiple historical trials, careful review of all study results and a robust meta-analysis are crucial to selecting an appropriate non-inferiority margin.

Assay Sensitivity and Constancy Assumption

Assay sensitivity is essential to non-inferiority trials as it demonstrates that had the study included a placebo arm, the active control – placebo difference would have been at least M1. The guidance outlines three considerations when determining if a trial has assay sensitivity.

  1. Historical evidence of sensitivity to drug effects
  2. The similarity of the new non-inferiority trial to the historical trials (the constancy assumption)
  3. The quality of the new trial (ruling out defects that would tend to minimize differences between treatments)

The constancy assumption in #2 above is that the non-inferiority study is sufficiently similar to the past studies with respect to the following design features.

  • The characteristics of the patient population
  • Important concomitant medications
  • Definitions and ascertainment of study endpoints
  • Dose of active control
  • Entry criteria
  • Analytic approaches

The presence of constancy is important to evaluate. For example, if a disease definition has changed over time or the methodology used in the historical trial is outdated the constancy assumption may be violated and the use of a non-inferiority design may not be appropriate. If all the design features are similar except the patient characteristics the estimate of the size of the control effect can be adjusted if the effect size is known in the patient sub-groups.

Benefits of non-inferiority trials

  • A non-inferiority trial is useful when a placebo controlled trial is not appropriate.
  • A non-inferiority trial may also test for superiority without concern about inflating the Type I error rate with care planning of the order in which hypothesis are tested. The reverse is not true; a superiority trial cannot claim non-inferiority.

Disadvantages of non-inferiority trials

  • Must be able to demonstrate assay sensitivity and the constancy assumption hold. This is especially difficult when medical practice has changed since the superiority trial (e.g. the active control is always used with additional drugs currently).
  • When the active treatment is not well established or historical trials have shown inconsistent results choosing a non-inferiority margin proves to be difficult.
  • If the treatment effect of the active control is small, the sample size required for a non-inferiority study may not be feasible
Download: Understanding Dose Finding Studies

OHRP Announces Revisions to the Common Rule

Posted by Brook White on Thu, Jan 26, 2017 @ 11:40 AM
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Shann Williams, Senior Director OperationsShann Williams has 10 years of experience managing clinical trials. She is a Sr. Director of Operations and the program director of the statistical and clinical coordinating center of the Transplantation Group for the division-wide consolidated coordinating center sponsored by the National Institute of Allergy and Infectious Disease (NIAID).  In addition, Shann serves as Rho's project management operational service leader, an internal expert sharing project management best practices, processes and training.

regulations, common ruleOn January 18, the Department of Health and Human Services (HHS) announced revisions to the Common Rule.  The intent of the revisions is to enhance protection for research participants while reducing the administrative burden associated with oversight.  This article provides background on the Common Rule, discusses the purpose of the revisions, provides a summary of the changes including which proposals from the review period were not incorporated, and discusses some anticipated impact of the final rule.  Stakeholders will need to be compliant by January 19, 2018.

Background

In 1991, the Federal Policy for the Protection of Human Subjects, generally referred to as the Common Rule, was released.  The original rule was based heavily on the Belmont Report of 1974 that sought to outline:

  1. The boundaries between biomedical/behavioral research and the accepted routine practice of medicine.
  2. The role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects.
  3. Appropriate guidelines for the selection of human subjects for participation in such research.
  4. The nature and definition of informed consent in various research settings.

The last revision took place in 2005.   Notice of proposed revisions to the Common Rule was published in September 2015 and more than 2100 comments were received, and some proposed changes were not adopted in the final rule.

The Common Rule applies to research using human subjects conducted or supported by HHS or 15 other federal agencies.  Pharmaceutical industry studies not conducted or supported by HHS may still fall under similar and largely redundant FDA regulations (e.g. 21 CFR 50, 21 CFR 54, 21 CFR 56).  Further, studies conducted or supported by HHS that need to comply with IND regulation would be subject to both the Common Rule and FDA regulations (for example, a study that will support changes to the label for an approved product). 

Revision Purpose

According the rule summary, the revision is “intended to better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators. These revisions are an effort to modernize, simplify, and enhance the current system of oversight.”

Research involving human subjects has grown and developed substantially over the last two decades. The revision cites examples of developments that include the increasing number and type of clinical trials, the use of electronic health data and other electronic data elements, as well as large data combined with more sophisticated analytical techniques.  These advances were not being matched by a comprehensive oversight system.  Per the revision, “The sheer volume of data that can be generated in research, the ease with which it can be used to identify individuals were simply not possible, or even imaginable, when the Common Rule was first adopted.”  The revision also references the President’s Precision Medicine Initiative as a consideration for proposed changes with the central tenant that participants in research should be active partners and not merely passive subjects.

Summary of Changes

The revision to the Common Rule includes the following:

  • Enacts new policies for what research subjects should be informed of during the informed consent process.  New requirements include:
    • A statement added to the consent form regarding whether a subject’s biospecimens – even if non-identified – may be used for commercial profit and whether the subject will or will not share in this profit.
    • Whether or not clinically relevant research results will be disclosed to subjects and, if so, how they will be disclosed.
  • Requires that one version of the informed consent form used during enrollment be posted for studies conducted or supported by the federal government on a federal website no later than 60 days after last patient, last visit. Responses to the revision suggested using Clinicaltrials.gov as the website to post these forms, but the federal website that will be used has not been determined.
  • Creates an expectation that informed consent forms include a succinct summary at the beginning of the document that includes information that would be most important to the person considering participation in the study such as potential benefits and risks, alternative treatments they should consider, and the purpose of the research.  According to Jerry Menikoff, Director of the Office of Human Research Protections (OHRP) at HHS, “Over the years, many have argued that consent forms have become these incredibly lengthy and complex documents that are designed to protect institutions from lawsuits, rather than providing potential research subjects with the information they need in order to make an informed choice about whether to participate in a research study. We are very hopeful that these changes and all the others that reduce unnecessary administrative burdens will be beneficial to both researchers and research participants.”
  • Allows obtaining a broad consent from subjects for unspecified future research as an option for investigators and requires that 12 elements be included (6 of these are specific to a broad consent).
  • Identifies new categories of research that may be exempt from a full IRB review based on the study’s risk profile. 
  • Requires that multi-center research use a single IRB for research that takes place within the United States.  This will become effective 3 years after publication of the final rule in 2020.
  • Enforces regulatory compliance for IRBs that are not operated by a Federal Wide Assurance holding institution.  Previously the rule held that institutions holding the FWA would be held responsible, thus increasing the reluctance of clinical sites to use a central IRB.
  • Alleviates the need for IRB continuing review of ongoing research for studies that were under expedited review, those studies that have completed study interventions and are in analysis, or are in observational follow-up combined with standard of care.

The final rule did not adopt several proposals being considered during the advanced notice of proposed rulemaking time period, including:

  • Requiring that non-identified biospecimens be subject to the Common Rule and require consent to be obtained for such specimens as well as imposing further restrictions under which a waiver of consent could be obtained for biospecimen research.  The proposed changes that received the most comments were regarding how the rule would impact biospecimens including the expanded definition of “human subject”.
  • Requiring that this policy expand to cover clinical trials that are not federally funded
  • Enforcing standard privacy practices for identifiable health information and biospecimens
  • Adding a list of activities that would meet the definition of “minimal risk” to provide more clarity around this definition
  • Requiring that the study exemptions to IRB review be documented and determined in a specific way (e.g., using a specific tool)

Predictions, Questions, and Things that Remain to Be Seen

  • The Common Rule document includes projections for quantitative savings and qualitative benefits from years 2017 – 2026. One theme of the NPRM public comments which led to the abandonment of the more controversial proposed changes in this final rule was the lack of details or as the Administrative Procedure Act calls them “terms or substance.”  The comments discussed a lack of quality deliverables as well as ambiguity around underlying tools, templates and concepts.  The revision cites examples of these not available for public comment at the time of the proposed rule-making: 1) broad consent templates; 2) standards for privacy protection; 3) list of eligible expedited procedures; and 4) study exemption decision tool.  Time will tell if the streamlined nature of the final rule as compared to the proposed changes will result in measurable deliverables and the projected quantitative & qualitative benefits.
  • In an ideal execution of the new rule, the requirement for multi-site U.S. research to use a single IRB would reduce costs and expedite the research.  Notably, the NIH also recently issued their policy on the use of a single IRBs for these types of studies.  However, we’ve had first-hand experience following this recent mandate.  Some clinical sites have been reluctant or unable to relinquish control over their research to a central IRB authority.  We have some studies that have had to go through both a central IRB and institutional site IRBs thereby increasing the study costs and timelines in direct contradiction to the goal of the revision.  Since the requirement change for the central IRB not held by a FWA-holding institution be in compliance with the rule will not be made effective until next year, there seems to be high potential that there will be increased costs and burden in the short-term.
  • In the same vein of thought, some clinical site IRBs may continue their current practices for full- and continuing reviews regardless of whether those studies meet the revised definition of being exempt from requiring them. Hopefully the changes will provide long-term benefits as more clinical sites become comfortable implementing the revisions and amending their institutional guidelines.
  • It is possible that institutions that support Common Rule-only, IND-only, and Common Rule/IND regulated projects will develop policies that generally assure compliance to both the CR and FDA regulations irrespective of which formally applies to any given study.
  • Providing study subjects their clinically relevant data has been a topic of discussion and an area of vested interest for some time now.  This is certainly a reasonable expectation for study subjects and one that the clinical research community wants to provide. The new rule does not require data to be provided to subjects, but the requirement to tell subjects whether they will receive this data may encourage the clinical research community to move in that direction more quickly.    However, there has been very little in terms of generally accepted methods or best practices in the absence of a formal guidance. In order to draft the appropriate consent form language per the updated rule, study-specific decisions will need to be made earlier during the protocol development phase which will impact CRF and database development as well as potentially have study design and randomization schema impacts.  Discussions will need to take place around what data is deemed to be “clinically relevant” (e.g., should all data for a given subject be provided or just this subset?), how distributing this data to study subjects may impact blinding considerations, appropriate timing of data sharing (e.g., after LPLV or after that specific subject completes the study), HIPAA considerations, providing the same data to their primary care providers, format and medium of the data to be shared, among many others factors for consideration. The research community will need to start discussing these impacts to ensure the statement included in the informed consent form will accurately convey the intent. 
  • In addition, it is uncertain what opinions are held by the new presidential administration and what impact those opinions might have.   
  • With regard to informed consent changes, there is clearly a desire to make ICFs easier for subjects to read, so they fully understand the benefits and risks of participation.  While the final rule sets that expectation, implementation of these changes will determine whether they provide the intended benefit. 
As with all new regulations, we’ll know more as stakeholders implement the various changes.  What do you think about the final rule?  Share your thoughts in the comments below.

The Rise of Electronic Clinical Outcome Assessments (eCOAs) in the Age of Patient Centricity

Posted by Brook White on Tue, Dec 06, 2016 @ 10:36 AM
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Lauren Neighbours, Clinical Research ScientistLauren Neighbours is a Research Scientist at Rho. She leads cross-functional project teams for clinical operations and regulatory submission programs and has over ten years of scientific writing and editing experience. Lauren has served as a project manager and lead author for multiple clinical studies across a range of therapeutic areas that use patient- and clinician-reported outcome assessments, and she worked with a company to develop a patient-reported outcome instrument evaluation package for a novel electronic clinical outcome assessment (eCOA).

Jeff Abolafia, Chief Strategist Data StandardsJeff Abolafia is a Chief Strategist for Data Standards at Rho and has been involved in clinical research for over thirty years. He is responsible for setting strategic direction and overseeing data management, data standards, data governance, and data exchange for Rho’s federal and commercial divisions. In this role, Jeff is responsible for data collection systems, data management personnel, developing corporate data standards and governance, and developing systems to ensure that data flows efficiently from study start-up to submission or publication. Jeff has also developed systems for managing, organizing, and integrating both data and metadata for submission to the FDA and other regulatory authorities.

patient centricityWith the industry-wide push towards patient-centricity, electronic clinical outcome assessments (eCOAs) have become a more widely used strategy to streamline patient data collection, provide real-time access to data (for review and monitoring), enhance patient engagement, and improve the integrity and accuracy of clinical studies.  These eCOAs are comprised of a variety of electronically captured assessments, including patient reported outcomes (PROs), clinician-reported and health-care professional assessments (ClinROs), observer reported outcomes (ObsROs), and patient performance outcomes administered by health-care professionals (PerfOs).  The main methods for collection of eCOA data include computers, smartphones, and tablets, as well as telephone systems.  While many companies have chosen to partner with eCOA vendors to provide these electronic devices for use in a clinical study, other sponsors are exploring “bring your own device (BYOD)” strategies to save costs and start-up time.  No matter what strategy is used to implement an eCOA for your clinical study, there are several factors to consider before embarking on this path.  

Designing a Study with eCOAs

The decision to incorporate an eCOA into your clinical study design is multifaceted and includes considerations such as the therapeutic area, the type of data being collected, and study design, but the choice can first be boiled down to 2 distinct concepts: 1) the need for clinical outcome data from an individual, and 2) the need for this data to be collected electronically. Thus, the benefits and challenges to eCOAs can be aligned with either or both of these concepts.

Regarding the first concept, the need for clinical outcome data should be driven by your study objectives and a cost-benefit analysis on the optimal data collection technique. Using eCOAs to collect data is undoubtedly more patient-centric than an objective measure such as body mass index (BMI), as calculated by weight and height measurements. The BMI calculation does not tell you anything about how the patient feels about their body image, or whether the use of a particular product impacts their feelings of self-worth. If the study objective is to understand the subjective impact of a product on the patient or health-care community, a well designed eCOA can be a valuable tool to capture this information. These data can tell you specific information about your product and help inform the labeling language that will be included in the package insert of your marketed product. Additionally, FDA has encouraged the use of PROs to capture certain data endpoints, such as pain intensity, from a patient population who can respond themselves (see eCOA Regulatory Considerations below). Of course, it’s important to note that the inherent subjectivity of eCOAs does come with its own disadvantages. The data is subject to more bias than other objective measures, so it’s critical to take steps to reduce bias as much as possible. Examples of ways to reduce bias include single- or double-blind trial designs, wherein the patient or assessor is not aware of the assigned treatment, and building in a control arm (e.g., placebo or active comparator) to compare eCOA outcome data across treatment groups.

Another important concept is the process for identifying and implementing the electronic modality for eCOA data collection.  Many studies still use paper methods to collect clinical outcome data, and there are cases when it may make more sense to achieve your study objectives through paper rather than electronic methods (e.g., Phase 1 studies with limited subjects).  However, several types of clinical outcome data can be collected more efficiently, at lower cost, and at higher quality with electronic approaches (e.g., diary data or daily pain scores).  From an efficiency standpoint, data can be entered directly into a device and integrated with the electronic data management system being used to maintain data collection balancing time and cost when considering paper or electronic clinical outcomes assessmentsfor the duration of the study.  This saves time (and cost) associated with site personnel printing, reviewing, interpreting, and/or transcribing data collected on paper into the electronic data management system, and it also requires less monitoring time to review and remediate data.  Additionally, paper data is often “dirty” data, with missing or incorrectly recorded data in the paper version, followed by missing or incorrectly recorded data entered into the data management system.  The eCOA allows for an almost instantaneous transfer of data that saves the upfront data entry time but also saves time and cost down the road as it reduces the effort required to address queries associated with the eCOA data.  Aside from efficiencies, eCOA methods allow for more effective patient compliance measures to be implemented in the study.  The eCOA device can be configured to require daily or weekly data entry and real-time review by site personnel prior to the next scheduled clinic visit.  Additionally, the eCOA system can send out alerts and reminders to patients (to ensure data is entered in a timely manner) and to health-care personnel (to ensure timely review and verification of data and subsequent follow-up with patients as needed).  The downsides to electronic data collection methods tend to be associated with the costs and time to implement the system at the beginning of the study.  It’s therefore essential to select an appropriate eCOA vendor  early who will work with you to design, validate, and implement the clinical assessment specifically for your study.

eCOA Regulatory Considerations

In line with the industry push for patient-focused clinical studies, recent regulatory agency guidance has encouraged the use of eCOAs to evaluate clinical outcome data.  The fifth authorization of the Prescription Drug User Fee Act (PDUFA V), which was enacted in 2012 as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), included a commitment by the FDA to more systematically obtain patient input on certain diseases and their treatments.  In so doing, PDUFA V supports the use of PRO endpoints to collect data directly from the patients who participate in clinical studies but also as a way to actively engage patients in their treatment.  The 2009 FDA guidance for industry on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims , further underscores this idea by stating “[the use] of a PRO instrument is advised when measuring a concept best known by the patient or best measured from the patient perspective.”  The 2013 Guidance for Industry on Electronic Source Data in Clinical Investigations  provides the Agency’s recommendations on “the capture, review, and retention of electronic source data” and is to be used in conjunction with the 2007 guidance on Computerized Systems Used in Clinical Investigations for all electronic data and systems used in FDA-regulated clinical studies, including eCOAs.  To support these efforts, the FDA has developed an extensive Clinical Outcome Assessment Qualification Program, which is designed to review and assess the design, validity, and reliability of a COA for  a particular use in a clinical study.  Furthermore, the newly formed Clinical Outcome Assessment Compendium  is a collated list of COAs that have been identified for particular uses in clinical studies.  The COA Compendium is further evidence of FDA’s commitment to patient-centric product development, and it provides a helpful starting point for companies looking to integrate these assessments into their clinical development programs. 

Before choosing an eCOA for your clinical development program, the following regulatory factors should be considered:

  • FDA holds COAs to the same regulatory and scientific standards as other measures used in clinical trials. Thus, it is advisable to refer to the Guidance for Industry on Patient-Reported Outcomes and the available information on the COA Assessment Qualification program and COA Compendium provided by the Agency when implementing eCOAs into your development program. If you plan to divert from currently available regulatory guidance, make sure to have a solid rationale and supporting documentation to substantiate your position.
  • The qualification of an eCOA often requires input from patients and/or health-care professionals to evaluate the effectiveness of the assessment. This input is necessary for the regulatory agency to determine whether the eCOA can accurately measure what it’s supposed to measure (validity) and to demonstrate it can measure the outcome dependably (reliability).
  • Data collected from qualified and validated eCOAs can be used to support product labeling claims. The key is to use an eCOA when it’s appropriate to do so and to make sure the eCOA supports your intended labeling claims because the instrument will be evaluated in relation to the intended use in the targeted patient population.
  • For the cases where an instrument was developed for paper based collection or an instrument is collected using multiple modes, it may be necessary to test for equivalence. This regulatory expectation is often required (especially for primary and secondary endpoints) to ensure that the electronic version of the instrument is still valid and data collected with mixed modes are comparable.

A CRO Can Help with your eCOA Strategy

CROs partner with sponsor companies to develop and execute their product development strategies.  In some cases, this involves implementing clinical outcome measures into a development program and then facilitating the interactions between the company and regulatory authorities to ensure adequate qualification of the COA prior to marketing application submission.  Whether or not you choose to engage a CRO in your development plan, consider seeking outside consultation from the experts prior to establishing your eCOA strategy to give you and your company the best chance of success.  

CROs Can Help:

  • Determine endpoints where eCOA data is appropriate
  • Determine the cost/benefit of electronic vs paper data capture
  • Determine the best mode of electronic data capture
  • Recommend eCOA vendors when appropriate
  • Perform equivalence analysis
  • Facilitate discussions with regulatory authorities
  • Manage the entire process of eCOA implementation

Webinar: ePRO and Smart Devices

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.

Webinar: Tips for a Smooth NDA Submission

Top Trends in Drug Development from This Year’s DIA Annual Meeting

Posted by Brook White on Tue, Jul 12, 2016 @ 02:41 PM
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During the last week of June, the Drug Information Association held its 52nd Annual Meeting in Philadelphia.  As one of the largest conferences in our industry, DIA covers a wide range of topics over the entire spectrum of drug development, and it would be nearly impossible to provide a comprehensive accounting of the meeting.  However, I will try to share the most notable trends and themes from the meeting.

Big Data

big data in drug developmentBig data was possibly the hottest topic this year.  Not only did FDA Commissioner Dr. Robert Califf participate in a panel session on the topic, but when listing his top four priorities, one of them was greater use of existing data in EMR/EHR systems.  At DIA, people were really talking about big data from a handful of sources—electronic medical records data, data from wearables, data from social and digital media and genomics (and other -omics) data.  FDA is taking a lead role in the use of big data and real world evidence through initiatives like Sentinel, which enhances the FDA’s ability to proactively monitor the safety of medical products on the market, and precisionFDA, a community platform for next generation sequencing (NGS) assay evaluation and regulatory science exploration.  Big Data is an idea that has been talked about for some time, but based on this year’s meeting it is clear we’ve moved beyond idea to reality.  For anyone wondering how soon we might see full genomic sequencing of all patients in a clinical trial, you will be interested to learn that the cost is now on par with a chest x-ray, Genentech has sequenced 30K genomes to date, and AstraZeneca recently entered into a partnership with Human Longevity to sequence 500K genomes over the next 10 years.

Patient Centricity is Still Big

patient-centricityPatient centricity was the theme of last year’s meeting, and continued to play a central role in this year’s meeting.  But while last year was big on ideas and optimism, this year saw early adopters sharing lessons learned from programs already up and running.  Patients and patient advocacy groups made up a noticeable group of attendees and were outspoken during sessions.  Several companies including Bristol Myers Squibb (BMS) and GlaxoSmithKline (GSK) shared specific programs and tactics they’ve been using to move to a more patient focused research model.  Some examples include creating frameworks that allow greater number of employees to engage with patients and the public about the work they are doing and developing minimum standards for patient engagement that reflect geographic and cultural differences.  From a regulatory perspective, patient-centricity made Dr. Califf’s list of his top four priorities.

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The Swinging Pendulum on Outsourcing

swinging pendulum on outsourcingFor many years now, it seemed the trend was always to more and more outsourcing with innovator companies keeping fewer and fewer activities in house.  Several of this year’s outsourcing sessions are hinting that the pendulum on that trend may be starting to swing back.  From internal frustrations with outsourcing groups, to dissatisfaction with vendors in terms of both quality and performance, to the failure of preferred provider relationships to deliver on expected savings and improvements, the talk from a number of pharmaceutical and biotech companies is that they are keeping more work in-house. That said, there certainly is not agreement among sponsors or vendors/suppliers on this issue.  Many pointed to issues at sponsor companies such as refusal to hear feedback from CROs on the feasibility of their budgets, timelines, or study designs as well and disagreement between outsourcing personnel and study team personnel about the providers being selected.

Drug Development as a Calling

DIA opened with keynote speaker Dr. Larry Brilliant, a physician and epidemiology who participated in the World Health Organization’s (WHO) successful small pox eradication program.  Dr. Brilliant talked through a number of health research and outreach efforts that have dramatically changed the world for the better, including the small pox and polio eradication programs, the development of electrolyte solutions to treat cholera and diarrhea, and more recently the efforts of the Carter Center to eradicate guinea worm.  He brought into sharp focus the idea that what each of us in the pharmaceutical industry does has the potential to change the world for the better.  The idea of drug development as a calling was furthered by Dr. Califf’s call to all of us to donate the information in our electronic health records for the betterment of research and medicine—a reminder that we should be willing to open ourselves up in the same way that we ask patients and research participants to do.  Finally, several of the patient-centricity speakers focused on the value of identifying employees who themselves were patients or care-takers of patients in their private lives in addition to being part of the research and development process.  These people are uniquely qualified to help us better understand the patients’ needs and experiences.

Greater Engagement by FDA

Finally, it was interesting to me to see the level of participation by the FDA in this year’s meeting. While they always send some presenters and a larger number come just to attend, this year did seem different. Dr. Califf presented in multiple sessions and was open and engaging during Q&A sessions. Additionally, numerous sessions included speakers and panelists from the FDA providing valuable insight into their point of view.

Did you attend DIA this year? If so, let me know what you thought.