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The Regulatory Strategist Toolbox: Clinical Endpoint Analysis Tools

Posted 27 September 2018 | By Meredith Brown-Tuttle, FRAPS, RAC 

The Regulatory Strategist Toolbox: Clinical Endpoint Analysis Tools

One of the critical parts of assembling a product’s “Strategy Playbook” or “Clinical Development Plan” is the researching and planning of clinical endpoints. This article discusses how to research endpoints, including tools to research them, how to organize the information and how to present the intelligence back to the team.

Endpoints are measures intended to reflect the effects (efficacy endpoints) or safety (safety endpoints) of a drug or device. They include assessments of clinical events (e.g., stroke, pulmonary exacerbation, venous thromboembolism), outcomes (e.g., what a final result of treatment long term, mortality, tumor resolution, cure of disease, remission), patient symptoms (e.g., pain, dyspnea, depression), measures of function (e.g., ability to walk or exercise), adverse events or surrogates of these effects or symptoms; clinical outcomes are considered the most reliable endpoint.1 One of the critical parts of the assembling either a product’s “Strategy Playbook” or “Clinical Development Plan” is the researching and planning of endpoints from Phase 1 through 3, including navigating through FDA’s understanding and interpretation of the laws and definitions (Table 1). 

Defining Efficacy Endpoints

Defining efficacy and their measurement through endpoints has been a dynamic process since the US 1962 Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act (FD&C Act), which was the first time a demonstration of efficacy (and endpoints to measure efficacy) was required.2,3 After the amendment, FDA spent the next decade defining, discussing, evolving and defending Sponsors’ lawsuits to arrive at what efficacy expectations should include (and some say the process is still ongoing).4

Prior to the 1962 Kefauver Harris Amendment:

  • efficacy was not clearly defined, safety of the product was relied upon
  • FDA was not involved in the definition of efficacy or claims of efficacy for products
  • companies would define efficacy (and subsequent endpoints) differently for similar products and both companies would claim efficacy of the product
  • companies let the individual physicians define efficacy and endpoints based on their patient population and subject interpretation (which would be combined as case studies into a marketing application resulting in many different endpoints used in the same study).

FDA’s definition and struggles to define efficacy served as a model for other regulatory agencies to adopt and use when formally establishing their own efficacy requirements; hence, the US focus in this article, but this information can be used in planning global trials with consultation of individual country regulations and guidance.

Why are endpoints needed?

Sound evidence of effectiveness is a crucial component of any regulatory agency’s benefit-risk assessment of a new product or use (i.e., a new indication). The need for an endpoint to measure the effectiveness of a drug stems from FDA’s need for substantial evidence, specifically called for in the 1962 Kefauver Harris Amendment and in 21 CFR 314.50 5.iii.v which requires that a marketing application contain, “data demonstrating substantial evidence of effectiveness for the claimed indications.” Substantial evidence was defined in section 505(d) of the FD&C Act as “evidence consisting of adequate and well-controlled investigations, including clinical investigations by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended or suggested in the labeling or proposed labeling hereof.”5

An adequate and well controlled (A&WC) study is defined in 21 CFR 314.126.b as a trial containing (summarized):

  • clear statement of objectives
  • methods of analysis which are adequate to assess the effects of the drug
  • use of a valid study design
  • defined patient population
  • randomization of patients
  • minimization of bias
  • Valid or Accepted Endpoints: the methods of assessment of subjects' response are well-defined and reliable. The protocol for the study and the report of results should explain the variables measured, the methods of observation and criteria used to assess response.

Clinical Benefit

FDA would like efficacy endpoints, if not already issued in a guidance document, to incorporate the mantra of “feels, functions or survive” which is collectively defined as clinical benefit. Clinical benefit is a clinically meaningful effect of an intervention, i.e., a positive effect on how an individual:

  • feels (e.g., symptom relief)
  • functions (e.g., improved mobility, improvement or delay in the progression of a disease or condition)
  • survives (e.g.,  time in delay to death in comparison to a natural history cohort)

Clinical benefit should be meaningful and understandable to prescribers and patients and can be measured directly or indirectly (indirect assessment needs justification for its value as a replacement for how patients survive, feel or function).6,7

Clinical Benefit Endpoints that have supported drug approval have included important clinical outcomes (e.g., increased survival, symptomatic improvement), but also have included effects on established (validated) surrogate endpoints (e.g., blood pressure, serum cholesterol).8,9

The caveat here is if there is no instrument to measure how a patient “feels” or “functions,” one’s company might need to develop and validate a patient reported outcome to capture and measure this.

Table 1. Overview of the Possible Clinical Trial Endpoints.
Term Definition
Endpoint

An endpoint is a primary or secondary outcome used to judge the effectiveness of a treatment; it is a precisely defined variable intended to reflect an outcome of interest that is statistically analyzed to address a particular research question. Synonyms include: outcome, variable, parameter or marker.

An endpoint typically specifies the type of assessments made, the timing of those assessments, the assessment tools used and possibly other details, as applicable, such as how multiple assessments within an individual are to be combined.10

An example of endpoints are survival, improvements in quality of life, relief of symptoms and disappearance of the tumor.11

Well-defined and reliable (21CFR 314.126)

Appropriate for the target population

Appropriate for the target indication

Adequate measurement properties, e.g., content validity: PRO development relies on patient input to support content validity12

Using end points that have already been approved by the regulatory authority makes the most sense, but if a new endpoint is being used, then it is necessary to prove that this endpoint is a valid measure of drug success.
Primary Endpoint Primary endpoints means the outcome or event that most accurately measures the benefit of the therapy/drug/intervention being studied (efficacy); this is the most clinically important endpoint. This is the main question the sponsor is most interested in answering and one that is capable of being answered (i.e., “Does the intervention alter mortality rates or change baseline blood pressure, the number of deaths, the difference in survival between the treatment group and the control group, disease progression or death). There is usually only one primary endpoint. Most of all the primary endpoint needs to be clinically meaningful and recognized by regulators as being clinically meaningful or confer clinical benefit (for new indications this can be a challenge) and should reflect the accepted norms and standards in the relevant field of research. There should be sufficient evidence that the primary variable can provide a valid and reliable measure of some clinically relevant and important treatment benefit in the patient population described by the inclusion and exclusion criteria.13-16
Secondary Endpoint

Typically, secondary endpoints are related to toxicity and undesired effects of the new therapy (safety) or to demonstrate additional effects on the disease or condition. The secondary questions need to support and relate to the primary objective and it used to demonstrate additional effects. For the primary objective of “Does the intervention alter mortality rates?” The secondary objective could look for cause of cardiac death, when death occurred or other cardiac incidents, such as:

  • coronary heart disease mortality
  • incidence of nonfatal myocardial infarction
  • incidence of stroke
  • reduction is risk factor

Secondary endpoints also may provide evidence that a particular mechanism underlies a demonstrated clinical effect (e.g., a drug for osteoporosis with fractures as the primary endpoint, and improved bone density as a secondary endpoint).17

Positive results on the secondary endpoints can be interpreted only if there is first a demonstration of a treatment effect on the primary endpoint.
Exploratory Exploratory endpoints may include clinically important events that are expected to occur too infrequently to show a treatment effect or endpoints that for other reasons are thought to be less likely to show an effect but are included to explore new hypotheses.18
Intermediate Clinical Endpoint In a regulatory context, an endpoint measuring a clinical outcome that can be measured earlier than an effect on Irreversible Morbidity or Mortality (IMM) and that is considered reasonably likely to predict the medical product’s effect on IMM or other clinical benefit. The intermediate clinical endpoint may be a basis for full approval if the effect on the endpoint is considered clinically meaningful. It also may be a basis for accelerated approval if the IMM effect is considered critical for use of the drug or for expedited access for medical devices intended for unmet medical need for life threatening or irreversibly debilitating diseases or conditions.
Multiple Primary Endpoints (Co-primary Endpoints)

It may sometimes be desirable to use more than one primary variable, each of which (or a subset of which) could be sufficient to cover the range of effects of the therapies.19

Multiple endpoints may be needed when determining that the drug confers a clinical benefit depends on more than one disease aspect or outcome being affected. Multiple endpoints may also be used when:

  • there are several important aspects of a disease or several ways to assess an important aspect
  • there is no consensus about which one will best serve the study purposes
  • an effect on any one will be sufficient as evidence of effectiveness to support approval

In some cases, multiple aspects of a disease may appropriately be combined into a single endpoint, but subsequent analysis of the components is generally important for an adequate understanding of the drug’s effect.20

Multiple primary endpoints become co-primary endpoints when it is necessary to demonstrate an effect on each of the endpoints to conclude that a drug is effective.

An example is treatment of migraine headaches; although pain is the most prominent feature, migraine headaches are also often characterized by the presence of photophobia, phonophobia, and nausea, all of which are clinically important.
Composite Endpoints

There are some disorders for which more than one clinical outcome in a clinical trial is important, and all outcomes are expected to be affected by the treatment.21

Rather than using each as a separate primary endpoint (creating multiplicity) or selecting just one to be the primary endpoint and designating the others as secondary endpoints, it may be appropriate to combine those clinical outcomes into a single variable or “composite” endpoint,” using a predefined algorithm (e.g., the rating scales used in arthritis, psychiatric disorders, and elsewhere).  This method is different than multiple primary endpoints and useful to study drugs if component events are infrequent and each component is clinically meaningful.22

Composite endpoints are often used when the goal of treatment is to prevent or delay morbid, clinically important but uncommon events (e.g., use of an anti-platelet drug in patients with coronary artery disease to prevent myocardial infarction, stroke and death).
Surrogate Endpoints

When direct assessment of the clinical benefit (or outcomes) to the subject through observing actual clinical efficacy is not practical, indirect criteria may be considered. A surrogate endpoint is a laboratory measure or a physical sign intended to be used as a substitute for a clinically meaningful endpoint and that is reasonably likely to predict clinical benefit (based on epidemiologic, therapeutic, pathophysiologic or other evidence per 21 CFR 314.510). Such surrogates are less well-established than surrogates in regular use, such as blood pressure for stroke, cholesterol for cardiovascular disease or HIV load for development of AIDS23 and new surrogates need to be validated. Relationships between clinical and surrogate variables for one product do not necessarily apply to a product with a different mode of action for treating the same disease.24,25

From a US regulatory standpoint, surrogate endpoints and potential surrogate endpoints can be characterized by the following level of clinical validation:

  • validated surrogate endpoint
  • reasonably likely surrogate endpoint
  • candidate surrogate endpoint26

A list of novel drugs approved using surrogate endpoints can be found on Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure

Pitfalls of using surrogate endpoints include:

  • uncertainty about clinical benefit
  • potential lack of correlation with outcome variable
  • lack of standardization or validation through multiple studies
  • missing long term data
  • possibility of undiscovered risks
  • less information about the occurrence of rare or delayed adverse events27

The level of evidence necessary to determine whether a surrogate is validated or likely to predict clinical benefit is made on a case by case basis by FDA.28
Reasonably Likely Surrogate Endpoint “An endpoint supported by strong mechanistic and/or epidemiologic rationale such that an effect on the surrogate endpoint is expected to be correlated with an endpoint intended to assess clinical benefit in clinical trials, but without sufficient clinical data to show that it is a validated surrogate endpoint. Such endpoints may be used for accelerated approval for drugs and potentially also for approval or clearance of medical devices. In the case of accelerated approval for drugs, postmarketing confirmatory trials have been required to verify and describe the anticipated effect on the irreversible morbidity or mortality or other clinical benefit.”29
Validated Surrogate Endpoint

“An endpoint supported by a clear mechanistic rationale and clinical data providing strong evidence that an effect on the surrogate endpoint predicts a specific clinical benefit. A validated surrogate endpoint can be used to support marketing approval of a medical or tobacco product in a defined context without the need for additional studies to demonstrate the clinical benefit directly. Although the term has been used in a conceptually broader way, from a U. regulatory standpoint, a validated surrogate endpoint almost always refers to a biomarker.”30

Validation information is available on the FDA website.
Biomarkers

“A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions. Molecular, histologic, radiographic or physiologic characteristics are types of biomarkers. A biomarker is not an assessment of how an individual feels, functions, or survives. Categories of biomarkers include:”

  • susceptibility/risk biomarker
  • diagnostic biomarker (example: stage a disease)
  • monitoring biomarker (monitoring a response to therapy)
  • prognostic biomarker
  • predictive biomarker (predict a response to a drug)
  • pharmacodynamic/response biomarker
  • safety biomarker31

FDA’s Biomarker and Qualification Information

Biomarkers Used as Outcomes List in Development of Approved Products (2007-2015)

Drug Development Too Program and Initiatives

What contribution is required from the RI strategist?

Regulatory strategists or intelligence professionals are called upon to help support the clinical portion of the strategy document or development plan by laying out the regulatory acceptable endpoints over the course of development. This means the RI strategist will need to:

  • research guidance documents available to understand required endpoints
  • research global past precedent to understand what the regulatory agency has allowed as primary and secondary endpoints for approved drugs in the same class or indication (if no guidance exists)
  • If a company is studying a new indication, Key Opinion Leaders (KOL) will be needed to help form and lead a Scientific Advisory Board (SAB) to help ensure the company is using the most relevant and measurable endpoints.
  • Endpoints for novel indication will typically come from literature and vetted with the KOLs and eventually the regulatory agency.
  • bring KOLs to regulatory meetings; there are typically several meetings with a regulatory agency (and sometimes advisory committee meetings) to reach agreement on novel endpoints
  • research the literature to understand the Standard of Care (SOC) in the therapeutic area across geographical regions
  • understand the changes in the SOC landscape, i.e., forthcoming changes in treatment paradigms as reported by the KOLs (i.e., what the baseline treatment paradigm is and what upcoming treatments or diagnostics methods are being developed over the next few years that should be anticipated and brought into the “Strategy Playbook”)
  • understand the competitive landscape (i.e., what are the endpoints competitors are using, especially if novel or not the same as in the guidance document, if any)
  • plan regulatory interactions with regulatory authorities to propose, discuss and negotiate endpoints, especially if it is a first in class or a new indication (and again, this is an iterative process and novel endpoint agreement does not usually happen in a single meeting)

Some things like researching KOLs is obvious—you look at Pubmed or advocacy groups, but where do you start with the endpoints? And what exactly do you collect, where do you find it and what should the presentation back to the team look like?

Evolution of Endpoints by Development Phase

Research should be performed and information organized according to phases of development to ensure a reasonable comparison (Table 2).To be able to recommend what endpoints to use at what stage, it is important to understand the evolution of endpoints over the clinical development of a product; from a safety emphasis in early studies to an efficacy endpoint in later studies. Endpoints differ by indication and change as disease treatment does.

Table 2. Endpoints by Phase
Phase of Development Typical Endpoints
Phase 1
  • Safety assessed after single and multiple dose administrations:
  • Adverse Events (AE)
  • Labs
  • Physical exam
  • Pharmacokinetics (PK)
  • Pharmacodynamic (PD) endpoints
Phase 2A
  • Safety assessed after single and multiple dose administrations:
  • Adverse Events (AE)
  • Labs
  • Physical exam
  • Pharmacokinetics (PK)
  • Dosing paradigm established
  • Exploratory efficacy endpoints used
Phase 2B
  • Safety assessments:
  • Adverse Events (AE)
  • Labs
  • Physical exam
  • Metrics used to establish efficacy further tested and refined, unless efficacy endpoints are dictated by a guidance document
Phase 3
  • Efficacy Endpoints refined in previous trials; divided into primary and secondary endpoints
  • Exploratory endpoints
  • Safety assessments:
  • Adverse Events (AE)
  • Labs
  • Physical exam

Endpoint Research

Where to Start—Free and Fee Tools

The first stop on any regulatory information gathering mission is to understand what tools are available (free versus fee tools), which ones are available to address a particular question and what each tool will provide for each piece of the puzzle. Table 3 provides a roadmap for endpoint exploration.

Table 3. Free and Fee Tools to Research Clinical Endpoints.
Tool Free Fee
Guidance Documents/Endpoint Specific Information
Clinical Trials Registries
Drug Approval Databases
Drug Label Information (approved Endpoints)
Drugs in Development
Therapeutic Area/Indication Background

Where to Start

Endpoint Analysis Information Blocking

Armed with the needed endpoint information and the tools to find it, the next step is to understand how to “block” the information so that it is usable for the analysis. There is a large morass of data to review and categorize, including literature, global guidance documents, past precedent (if available) and the endpoints of trials currently underway as these have typically been vetted (or at least discussed) with the agency for the study being conducted. Table 4 provides information to collect for each endpoint.

Table 4. Endpoint Information Needed to Serve as a Basis for Analysis.
Information Needed on Each Endpoint Where to Find it Why
Regulatory Precedence and Acceptance

Previous regulatory filings (Drugs@FDA (or similar))

Clinicaltrials.gov listing

Elsevier’s PharmaPendium
  • Understand if the proposed endpoints will be accepted or if you will need to work with regulators to gain their acceptance
Current Use of Endpoint in Research

Country specific guidance documents

Journal articles

Drugs@FDA (or similar)
  • Understand what endpoints are being explored as primary, secondary and exploratory endpoints by researchers in the field as the scientific information could change during the development process
What does endpoint really measure?

Journal articles

Drugs@FDA (or similar)
  • Understand how to measure the indication.  Sometimes endpoints do not measure what you need them to and then you need to reevaluate the endpoint
  • Some endpoints measure what you want, some what you need for regulatory requirements and others what you need to understand what endpoints most appropriately measure activity in your indication
Positive and negative views on endpoint use

Journal articles

Drugs@FDA (or similar)
  • What are the pros and cons to using the proposed endpoints? 
  • Is the scientific information changing and will the endpoints be changing over the timeframe? 
Endpoint validated?

Journal articles

Drugs@FDA (or similar)
  • Is there a new indication that has a new endpoint? 
  • Is there a new way to measure an endpoint?
  • What are the endpoints that have been used to measure the indication in the literature by researchers?
  • What is the acceptance or perception of the endpoints by regulators?
  • What work will the sponsor need to conduct to validate the endpoint?
  • Does validation need to be done prior to use in a study or during the conduct of the study?
  • Will a patient reported outcome be needed or created?
Inclusion/Exclusion Population

Journal articles

Drugs@FDA (or similar)

Elsevier’s PharmaPendium

Country specific guidance documents
  • The indication and patient population is defined by the study’s inclusion and exclusion criteria; this needs to be defined carefully as it will affect the outcome of the development program

Only the endpoints that are used most frequently or have past regulatory precedence should have an in-depth analysis conducted; all other should be high level reporting until the team agrees more analysis is needed. Once the information is acquired to define the output, which can differ vastly depending on the free or fee tools used, start constructing the output.

Endpoint Analysis

Steps for Information Gathering and Initial Analysis

Endpoint Analysis: Free

  • Go to drugs.com and find out what other drugs are in the same class and/or indication; utilize in house expertise as well to help refine the list
  • Add drug names to list in an excel spreadsheet
  • Cull endpoint information initially from the label—cannot find the label in drugs.com or Drugs@FDA? Go to the FDA Online Label Repository where labels are archived
  • Refine list, if in oncology, with the help of NIC databases (Cancer Drug Approval Endpoints, Efficacy Endpoints in Oncology Clinical Trials)
  • Research available global guidance documents in indication (Intelligence Tools, Links and Resources); cull endpoints recommendation into excel spreadsheet
  • Pull the Summary Basis of Approvals (Intelligence Tools, Links and Resources) in the countries of choice based on research
  • Pull out the endpoints used for all past precedent drug into an excel worksheet by phase of development
  • From the medical or administrative section (with meeting minutes), cull information on endpoints discussions and issues with it such as lack of validation
  • Research current clinical trials being conducted in a clinical trial registry for both the indication and class of drugs; add these to the growing spreadsheet (Table 5) (sometimes it helps to do this step first prior to all other activities):
  • Further refine the search by phase of development and download just the trials in Phase 1, Phase 2, etc., and review those items
  • Look at map of countries and the location of sites being used in the studies
  • Look at synonyms for the disease and review other trials possibly associated with the same disease, but called by a different name
  • Organize by drug name, stage of development and endpoints
  • Research the following literature on PubMed:
  • recent trials in the indication and endpoints used
  • SOC
  • Evolution in changes in the SOC
  • KOLs
  • Download/purchase literature for in-depth review
  • Utilize indication specific (if any) advocacy groups to help refine current endpoints being used by KOLs or to help provide a literature jumping off point; this can be done through an SAB or one on one meetings
  • Analyze the list of endpoints, what are the typical endpoints used, what are the least typical and do a deep dive into the endpoints used most often so there is greater clarity on them for team discussion.
  • Put in a format to present the findings to the development team, for group discussion (Table 5) and rate from most frequently used, least used and emerging endpoints
  • This list needs to be reviewed with the Strategy Team and further refined as the Playbook is developed (i.e., this process might need to be used a few times and vetted with experts and the regulators).
Table 5. Clinicaltrials.gov Output Into Excel.*
Title Conditions Interventions Study Designs Outcome Measures Phases Enrollment and Study Type
MLN0128 in Recurrent/Metastatic Merkel Cell Carcinoma Merkel Cell Carcinoma Drug: MLN0128

Intervention Model: Single Group

Assignment

Masking: None (Open Label)

Primary Purpose: Treatment

Maximum Tolerated Dose (MTD)

Overall Response Rate (ORR)

Overall Survival (OS)

Progression-Free Survival (PFS)

Adverse Events (AEs)

Response Biomarkers, including p4EBP1, PSK6, pCAD and Merkel cell polyomavirus (MCV)

Large T antigen (LT) and small T antigen (ST)

Phase 1

Phase 2

34

Interventional
F16IL2 Plus Paclitaxel in Metastatic Merkel Cell Carcinoma Merkel Cell Carcinoma

Drug: Arm A: F16IL2 in combination with paclitaxel

Drug: Arm B: Paclitaxel

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: None (Open Label)

Primary Purpose: Treatment

Efficacy of F16IL2 in combination with paclitaxel vs. paclitaxel monotherapy (RECIST v1.1, irRC)

Overall survival rate

Treatment efficacy (ORR, DCR)

Safety and tolerability of the combination treatment with F16IL2 and paclitaxel

 Phase 2

90

Interventional
A Proof-of-Concept Trial of GLA-SE in Patients With Merkel Cell Carcinoma Merkel Cell Carcinoma Biological: GLA-SE

Intervention Model: Single Group Assignment

Masking: None (Open Label)

Primary Purpose: Treatment

Safety and feasibility

Clinical efficacy and immunogenicity

 Phase 1

10

Interventional
Adjuvant Therapy of Completely Resected Merkel Cell Carcinoma With Immune Checkpoint Blocking Antibodies Versus Observation Merkel Cell Carcinoma

Drug: Ipilimumab

Drug: Nivolumab

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: None (Open Label)

Primary Purpose: Treatment

Disease-free survival (DFS) at 12 months

Number of adverse events

Overall survival rate at 12 months

DFS rate at 12 months

 Phase 2

177

Interventional
Study of the Drug Ipilimumab for Metastatic Merkel Cell Carcinoma Merkel Cell Carcinoma Drug: Ipilimumab

Allocation: Non-Randomized

Intervention Model: Single Group Assignment

Masking: None (Open Label)

Primary Purpose: Treatment

Overall survival at 12 months with ipilimumab treatment

Determine the best overall response rate, median survival, disease-specific survival and progression free survival

Determine median survival, disease-specific survival and progression nfree survival

 Phase 2

0

Interventional
QUILT-3.009: Study of aNK Infusions in Combination With ALT-803 in Patients With Stage III (IIIB) or Stage (IV) Merkel Cell Carcinoma (MCC)

Stage IIIB Merkel Cell Carcinoma

Stage IV Merkel Cell Carcinoma

 Biological: aNK (NK-92)

Intervention Model: Single Group Assignment

Masking: None (Open Label)

Primary Purpose: Treatment

Progression Free Survival

Overall Response Rate

Time to disease progression

Overall survival

Safety and tolerability of aNK in combination with ALT-803

Quality of life assessment

 Phase 2

24

Interventional
*Need to Specify Fields to Download.

Endpoint Analysis: Fee

Figure 1. Organized Endpoint Output for BizInt Smart Charts (Combined Output from a Variety of Clinical Registries).

Brown-Tuttle-Fig-1.jpg
  • Go to PharmaPendium, input the indication and class as search terms, cull results for a list of drugs approved for indication and class and endpoints in medical reviews; utilize in house expertise to help refine the list; put results into an excel spreadsheet
  • Pull out the endpoints used for all past precedent drug into an excel worksheet, by phase of development
  • From the medical or administrative section (with meeting minutes) cull information on endpoints discussions and issues with it such as lack of validation
  • Research available global guidance documents in indication; cull endpoints recommendation into excel spreadsheet using Tarius or Clarivate Analytics Cortellis
  • Ask Nerac to conduct a literature search for you looking at SOC, KOLs, emerging treatments and endpoints used for indication
  • Or ask a Librarian to conduct the literature search for you
  • Ask librarian or literature search service to download/obtain literature
  • Review and put results into an excel spreadsheet
  • Analyze the list of endpoints, put in a format to present your findings to the development team, for group discussion

Regulatory Pathway Dictated by Type of Endpoint Used

Something to keep in mind when finalizing and incorporating endpoints into a strategy, the type of endpoint selected can dictate the regulatory approval pathway that needs to be followed. Review Table 6 to ensure alignment with regulatory expectations.

Table 6. Endpoints and Predicted Regulatory Pathway.
Type of Endpoint What it Does Regulatory Pathway
Clinical Benefit How a patient feels, functions or survives Regular*
Validated Surrogate Recognized as validated through multiple definitive studies Regular*
Surrogate Reasonably likely to predict clinical benefit Accelerated Approval
*Could be accelerated or priority review based on the unmet medical need or seriousness of indication.32

Communicating the Data Back to the Stakeholders

Once the needed information is available to define the output, which can differ vastly depending on the free or fee tools used and the specific indication, begin constructing the output and understand what is needed for the output. One of the biggest issues in analyzing data, since it is so onerous, is the presentation back to the team and deciding the most efficient form is should take. On the backend, there is a lot of data that needs to be cleaned, merged or manually manipulated and since it is disparate, it can be very difficult to summarize, especially endpoints. Most teams want a high-level analysis that is interactive so as to answer immediate questions and an excel spreadsheet does not have visual appeal; this is where a “fee” product really is helpful in presenting a brightly colorful and interactive output.

Case Study—Merkle Cell Carcinoma

The following case study discusses the indication of the rare disease Merkle Cell Carcinoma (MCC) and demonstrates how to put the above information into practice. Note: only one drug has been approved for this indication [BAVENCIO [AVELUMAB]] (approved 23 March 2017).

New Regulatory Intelligence Tool

BizInt Smart Charts Drug Development Suite is purpose-built software designed to facilitate creating, customizing and distributing tabular reports from selected clinical trial, drug pipeline and biomedical journal databases. Reflecting more than 20 years of feedback from users in pharmaceutical and biotech companies, it replaces the need to write complicated macros and manually manipulate data in Excel and Word. Data from supported databases (see below) is imported and formatted into tables, and the fields/columns included in your report can be changed at any time. BizInt Smart Charts automatically identifies the same trial across different databases and the same drug across pipeline databases and has tools to merge different database records on the same trial into a single integrated row in your report.

A second tool, VantagePoint - Smart Charts Edition, has the ability to further refine the data, extract terms and create visualizations for PowerPoint presentations. Table 7 provides an overview of the databases that BizInt Smart Charts can pull from to help compile endpoint information.

Table 7. BizInt Smart Charts Drug Development Suite—Supported Databases.
Supported Clinical Trial Databases Supported Pipeline Databases Supported Biomedical Journal Databases

Registry:
Clinical Trials.gov
EU Clinical Trials Registry
WHO ICTRP

Commercial:
Citeline Trialtrove
Adis Clinical Trials Insight
Cortellis Clinical Trials

Citeline Pharmaprojects
Clarivate Analytics Cortellis
IMS R&D Focus
Adis R&D Insight
Clarivate Integrity

Medline/PubMed
BIOSIS
EMBASE

BizInt Smart Charts was used to collect endpoint information from a variety of Clinical Trial Registries for MCC and this was compared with the collection and analysis times done without the tool (Table 8).  Overwhelmingly, the tool shaved more than 100 hours off of the task at hand (two weeks of work.)

Table 8: Mining Clinical Trial Registry Data for Endpoints—Time Comparison of the Free and For Fee Tools
Steps Taken Tools Used
Free Time Fee Time
Search databases for “Merkle Cell Carcinoma” and download results to excel spreadsheet

WHO—ICTRP Search Portal

Drugs@FDA Database

 10 min 10 min

Open up the spreadsheets and combine the trials
  • Google Worksheets
  • MS Excel
 5 min
  • BizInt Smart Charts

(Figure 1)

 2 min

Go through and remove the duplicates and/or merge the information for the same trials listed in multiple databases
  • Google Worksheets
  • MS Excel
 100+ min
  • BizInt Smart Charts
 5 min
  • Delete or move around fields so that pertinent information is displayed in first few rows
  • Hide rows so that they are still available but not distracting your analysis
  • Google Worksheets
  • MS Excel
 45+ min
  • BizInt Smart Charts
 20
  • Analyze what is pertinent to your program to be able to make recommendations to the team

Brain power and experience

 200+ min

Brain power and experience

 200+ min
  • Put together the information in a way easily incorporated into the Strategy Playbook
  • Google Worksheets
  • MS Excel
 60+ min
  • PowerPoint
  • BizInt Smart Charts
 30 min
  • Put together information in a PowerPoint Slide for presentation to the team
  • Google Worksheets
  • MS Excel
  • PowerPoint
 60+ min
  • PowerPoint
  • BizInt Smart Charts
 30 min
Total Time 480+ min ~297 min

Case Study Conclusion

Overall, while some of the steps are the same, the fee tools do provide quicker information output which can lead to quicker analysis and feedback to the team. BizInt Smart Charts and VantagePoint significantly cut down on the time it took to research endpoints making the time to respond to the team quicker and the output visually pleasing (which would have taken a lot longer to achieve manually) and interactive, which really worked well for the team and because questions were able to be answered on the spot versus looking through a pile of notes. 

Summary

As a parting note, remember the “Strategy Playbook” must be reviewed on an annual basis as scientific data and the requirements for a program change over time, so keeping complete notes and output are important to help evaluate data as it evolves.

References

  1. Multiple Endpoints in Clinical Trials. Guidance for Industry. January 2017. FDA website https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm536750.pdf. Accessed 21 September 2018.
  2. Federal Food, Drug, and Cosmetic Act (FD&C). FDA website. https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/FederalFoodDrugandCosmeticActFDCAct/default.htm. Accessed 21 September 2018.
  3. Kefauver-Harris Amendments Revolutionized Drug Development. FDA website. https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm322856.htm. Accessed 21 September 2018.
  4. Carpenter D. Reputation and Power. Organizational Image and Pharmaceutical Regulation at the FDA. Princeton University Press. https://press.princeton.edu/titles/9205.html. Accessed 21 September 2018.
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  6. BEST (Biomarkers, EndpointS, and other Tools) Resource. May 2018. FDA-NIH Biomarker Working Group. https://www.ncbi.nlm.nih.gov/books/NBK326791/pdf/Bookshelf_NBK326791.pdf. Accessed 21 September 2018.
  7. Defining Clinical Benefit in Clinical Trials: FDA Perspective. Presentation by Jessica J. Lee, MD, MMSc. https://celiac.org/wp/wp-content/uploads/2015/04/great3-07.pdf. Accessed 21 September 2018.
  8. Guidance for Industry. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. May 2007. FDA website. https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf. Accessed 21 September 2018.
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  27. FDA Regulatory Considerations for NASH Clinical Trial Endpoints. Presentation by Stephanie O. Omokaro, PhD. Global NASH Congress. https://www.slideshare.net/JaneWilliams25/fda-regulatory-considerations-for-nash-clinical-trial-endpoints
  28. Sanyal AJ, Friedman SL, McCullough AJ  and Dimick-Santos L. “Challenges and Opportunities in Drug and Biomarker Development for Nonalcoholic Steatohepatitis.” Findings and recommendations from an American Association for the Study of Liver Diseases and FDA  Joint Workshop. https://www.ncbi.nlm.nih.gov/pubmed/25557690. Accessed 23September 2018.
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About the Author

Meredith Brown-Tuttle, RAC, FRAPS, is the principal consultant for Regulatorium, a company specializing in regulatory intelligence, writing and strategy. She is the author of IND Submissions: A Primer, published by Barnett, Regulatory Intelligence 101, published by RAPS, numerous articles and serves as chair of the RAPS Editorial Advisory Committee. She can be reached at theregulatorium@gmail.com.

Cite as: Brown-Tuttle M. “The Regulatory Strategist Toolbox: Clinical Endpoint Analysis Tools.” Regulatory Focus. September 2018. Regulatory Affairs Professionals Society.

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