The Regulatory Strategist Toolbox: Clinical Endpoint Analysis Tools

Feature Articles | 27 September 2018 | Citation

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	Health authority websites Cancer Drug Approval Endpoints Efficacy Endpoints in Oncology Clinical Trials	RAPS Regulatory Focus Pink Sheet IQVIA’s Tarius Clarivate Analytics Cortellis
Clinical Trials Registries	www.Clinicaltrials.gov EU Clinical Trials Register www.clinicaltrialsregister.eu/ctr-search/search ICTRP Search Portal - World Health Organization	Informa Pharma Intelligence—Trialtrove Elsevier’s PharmaPendium
Drug Approval Databases	Drugs@FDA European Public Assessment Report (EPAR) Health Canada Summary Basis of Decision information through Drug and Health Product Register (DHPR) Australian Public Assessment Reports for prescription medicines (AusPARs) Oncology specific drugs and their uses (National Cancer Institute Drug Dictionary)	Informa Pharma Intelligence—BioMed Tracker Informa Pharma Intelligence—Pharmaprojects Elsevier’s PharmaPendium
Drug Label Information (approved Endpoints)	Drugs.com Health authority label websites	Elsevier’s PharmaPendium
Drugs in Development	CenterWatch—Drug Approvals by FDA Division and Year Clinicaltrials.gov Company Press Releases and Websites Drugs.com—New Drug Applications FierceBiotech (indication-specific press releases) Google Searches Hoovers FDA Advisory Committee Meeting Background Information Packages	Centerwatch Drugs in Clinical Trial Database Informa Pharma Intelligence—BioMed Tracker Informa Pharma Intelligence—Meddevicetracker Informa Pharma Intelligence—Medtrack Informa Pharma Intelligence—Pharmaprojects Elsevier’s PharmaPendium (Approved Drugs and Labels) Springer HealthCare Adis Insight Clarivate Analytics Cortellis Product Approval Tables
Therapeutic Area/Indication Background	Advocacy Groups CenterWatch—hot topics, advocacy groups, recent papers grouped by therapeutic area DrugWatch Google Searches National Library of Medicine’s Medline (journal articles, meta-analysis articles) National Cancer Institute (NCI) Drug Dictionary of Cancer Terms National Comprehensive Cancer Network National Institute of Arthritis and Musculoskeletal and Skin Disease Therapeutic Background US FDA Information by Drug Class WebMD Physicians or Key Opinion Leaders Previous drug submissions for approved products can provide an overview of the indication	Datamonitor Healthcare Indication Profile from BioMed Tracker National Library of Medicine’s Medline Market Analysis/Research Reports Martindale: the Complete Drug Reference Truven Health Analytics Micromedex Solutions Elsevier’s PharmaPendium Physician’s Desk Reference

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

Use clinical trial information specific databases, such as: Citeline Trialtrove, Adis Clinical Trials Insight or Cortellis Clinical Trials Intelligence and put it into an excel spreadsheet or use BizInt (Figure 1) to help organize the information.

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

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

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
Steps Taken	Free	Time	Fee	Time
Search databases for “Merkle Cell Carcinoma” and download results to excel spreadsheet	Clinicaltrials.gov EU Clinical Trials Register www.clinicaltrialsregister.eu/ctr-search/search WHO—ICTRP Search Portal Drugs@FDA Database	10 min	Clinicaltrials.gov EU Clinical Trials Register WHO—ICTRP Search Portal	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

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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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