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Meredith Brown-Tuttle, FRAPS, RAC
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 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:
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.
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):
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:
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.
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.
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:
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.
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:
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.
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).
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:
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:
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
“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.
“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:”
FDA’s Biomarker and Qualification Information
Biomarkers Used as Outcomes List in Development of Approved Products (2007-2015)
Drug Development Too Program and Initiatives
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:
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?
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.
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.
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.
Previous regulatory filings (Drugs@FDA (or similar))
Clinicaltrials.gov listing
Elsevier’s PharmaPendium
Country specific guidance documents
Journal articles
Drugs@FDA (or similar)
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.
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
Drug: Arm A: F16IL2 in combination with paclitaxel
Drug: Arm B: Paclitaxel
Allocation: Randomized
Intervention Model: Parallel Assignment
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
90
Intervention Model: Single Group Assignment
Safety and feasibility
Clinical efficacy and immunogenicity
10
Drug: Ipilimumab
Drug: Nivolumab
Disease-free survival (DFS) at 12 months
Number of adverse events
Overall survival rate at 12 months
DFS rate at 12 months
177
Allocation: Non-Randomized
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
0
Stage IIIB Merkel Cell Carcinoma
Stage IV Merkel Cell Carcinoma
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
24
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.
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.
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).
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.
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.)
WHO—ICTRP Search Portal
Drugs@FDA Database
Open up the spreadsheets and combine the trials
(Figure 1)
Go through and remove the duplicates and/or merge the information for the same trials listed in multiple databases
Brain power and experience
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.
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.
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.