FDA PRO Final Guidance v Draft Version

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The purpose of this article is to provide Sponsors and CROs with a point-by-point review
of the differences between the Final FDA PRO Guidance and the Draft, highlighting the
choices made by FDA during the 3 years following the Draft PRO Guidance. These choices
reveal the FDA deliberations and resulting emphasis, and we also suggest in our review
what some of the differences might imply. Note that where terms appear highlighted
or emphasized in quotes from the Final Guidance, the emphasis has been done in the
original FDA document.

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FDA PRO Final Guidance v Draft Version

  1. 1. The Difference between the FDA Draft Guidance and Final Guidance: How these modifications affect Sponsors and CROs Contents The FDA Final Guidance1: Key Considerations for PRO or ePRO Instrument Sponsors Collecting PRO and ePRO Data PRO instrument review 2 Clinical researchers who gather data directly from patients have anticipated the FDA Final PRO Guidance for more than 3 years. The document released in December 2009 PRO instrument definition 2 provides constructive support for collecting PRO and ePRO (electronic PRO) data with PRO instruments measure concepts 2 scientific rigor. It establishes that FDA reviewers will evaluate protocols with respect to the targeted labeling claims, an endpoint model, conceptual framework of PRO PRO instrument validation 3 instruments and the content validity of PRO items. Each of these key elements is defined and explained in the Final Guidance itself. The collaborative effort extended in Reasons for changing a PRO instrument 4 developing the Final PRO Guidance should help clinical researchers to rely on patient Evaluating a modified PRO instrument 5 self-reported information in support of market authorizations and advertising claims. Specific concerns when using ePRO 8 The purpose of this article is to provide Sponsors and CROs with a point-by-point review instruments of the differences between the Final FDA PRO Guidance and the Draft, highlighting the choices made by FDA during the 3 years following the Draft PRO Guidance. These choices Proving that the concept is measurable, 9 reveal the FDA deliberations and resulting emphasis, and we also suggest in our review and the instrument is the measure of what some of the differences might imply. Note that where terms appear highlighted the concept or emphasized in quotes from the Final Guidance, the emphasis has been done in the Endpoint Data original FDA document. The endpoint model 3 The focus of the Final Guidance has been altered from a review of best practices for PRO instrument development to FDA review considerations for PRO instruments, establishing Safety outcomes are not endpoints 3 guidelines for evaluating existing, modified or newly created [e] PRO instruments. The Final Guidance also provides more precise directives on how to leverage PRO Proof of data entry times required 5 for labeling claims, and greater direction to Sponsors and CROs. The Final Guidance Concerns about unintentional and 6 recommends that Sponsors should begin [PRO or ePRO] instrument development and intentional unblinding evaluation early in medical product development, and should also engage the FDA in a discussion about a new or unique PRO [or ePRO] instrument before confirmatory clinical Missing data from patient withdrawal 6 trial protocols are finalized. Design requirements for multiple 7 3 Key Takeaways: endpoints 1. The Final Guidance emphasizes three aspects of PRO instruments used to support Interpreting data beyond statistical 7 claims in approved medical product labeling: the conceptual framework, endpoint significance model, and content validity. A proxy-reported outcome is not a PRO 10 2. The Guidance includes an Appendix to help Sponsors prepare a dossier to be submitted to FDA that explains and justifies the PRO instruments planned for PRO and ePRO Collection Process an investigation. Enhanced Wheel & Spokes diagram 4 3. PRO instrument development and use should be completed before commencing 5 criteria used to demonstrate 5 confirmatory trials. PHT suggests that Sponsors discuss planned PRO measures content validity with us during the development phase so that we can help them optimize item and instrument selection to suit the trial objectives and to obtain scientifically compelling How to demonstrate a treatment 9 data directly from patients as they experience a new medical therapy. benefit It is critical that the clinical trial protocol define the endpoint measures and the criteria Appendix as PRO and ePRO dossier 9 for the statistical analysis and interpretation of results, including a specification of the conditions for a positive clinical trial conclusion, because determination of these criteria and conditions after data are unblinded will not be credible. 1 http://www.phtcorp.com/
  2. 2. 2The Difference between the FDA Draft Guidance and Final Guidance:How these modifications affect Sponsors and CROs Key Learnings Guidance for Industry (Final) Draft Guidance February 2006 for Sponsors and CROs December 2009 PRO Sponsors and CROs who plan to rely [Lines 21-24] This guidance describes [Section I] This Guidance describes instrument on PRO and ePRO instruments to how the FDA evaluates patient-reported how the Food and Drug Administration review support claims in approved medical outcome (PRO) instruments used as (FDA) reviews and evaluates existing, product labeling will know how FDA effectiveness endpoints in clinical modified, or newly created patient- will review them. trials. It also describes our current reported outcome (PRO) instruments thinking on how sponsors can develop used to support claims in approved and use study results measured by medical product labeling. PRO instruments to support claims in approved product labeling. PRO Sponsors should define how their PRO [Lines 45-49] In particular, the [Section I] A PRO instrument (i.e., a instrument instruments measure treatment benefit, term instrument refers to the actual questionnaire plus the information definition and should establish suitability of the questions or items contained in a and documentation that support its measures before patient enrollment in questionnaire or interview schedule use) is a means to capture PRO data confirmatory trials. along with all the additional used to measure treatment benefit or information and documentation risk in medical product clinical trials. that supports the use of these items [Section III.B. paragraph 5] We suggest in producing a PRO measure (e.g., that an instrument’s measurement interviewer training and instructions, properties be well established before scoring and interpretation manual.) enrollment begins for confirmatory clinical trails. Therefore, sponsors should begin instrument development and evaluation early in medical product development, and engage the FDA in a discussion about a new or unique PRO instrument before confirmatory clinical trial protocols are finalized. PRO A Dossier explains how a concept being [Lines 82-89] Note, however, that PRO [Section II, paragraph 1] In clinical instruments measured relates to clinical benefit, instruments that measure a simple trials, a PRO instrument can be used measure endpoints and claims. concept may not be adequate to to measure the effect of a medical concepts Sponsors and CROs may elect to utilize substantiate a more complex claim. intervention on one or more concepts Section III as their protocol outline for For example, PRO-based evidence of (i.e., the thing being measured, such collecting PRO and ePRO, since it lists improved symptoms alone generally as a symptom or group of symptoms, key considerations for content: is not sufficient to substantiate a effects on a particular function or group claim related to improvement in a of functions, or a group of symptoms • Endpoint Model patient’s ability to function or the or functions shown to measure the • Choice of PRO Instrument patient’s psychological state. Rather, severity of a health condition.) • Conceptual Framework of a PRO to substantiate such a general claim, Instrument a sponsor should develop evidence to • Content Validity show not only a change in symptoms, • Reliability, Other Validity, and Ability but how that change translates into to Detect Change other specific endpoints such as • Instrument Modification ability to perform activities of daily • PRO Instruments Intended for Specific living, or improved psychological state. Populations Accordingly, many PRO instruments are specifically designed to assess both symptoms and other possible consequences of treatment.
  3. 3. 3The Difference between the FDA Draft Guidance and Final Guidance:How these modifications affect Sponsors and CROs Key Learnings Guidance for Industry (Final) Draft Guidance February 2006 for Sponsors and CROs December 2009 The endpoint Sponsors and CROs should define [Lines 791-798] A PRO instrument could [Section II.A.] Sponsors should define model the role of a PRO or ePRO endpoint be the primary endpoint measure of the the role a PRO endpoint is intended to within the protocol, and plan the study, a co-primary endpoint measure play in the clinical trial (i.e., a primary, endpoint model. in conjunction with other objective or key secondary or exploratory endpoint) physician-related measurements, or so that the instrument development a secondary endpoint measure whose and performance can be reviewed in analysis would be considered according the context of the intended role, and to a hierarchical sequence. appropriate statistical methods can be planned and applied. It is critical to plan these approaches in what can be called an endpoint model. Safety Sponsors and CRO trial designers [Lines 164-165, Table 1] The intended [Section III.B.] Claims representing outcomes and should be wary of combining efficacy use of the measure is general concepts often are not endpoints measures and measures of adverse supported, even though the PRO consequences to measure a general • To define entry criteria for study instrument was developed to measure concept. Instead, it is recommended populations the general concepts, because the that they separate measures • To evaluate efficacy instrument may not distinguish adverse of treatment effectiveness from • To evaluate adverse events side effects of treatment that affect measures of that treatment’s adverse the general concept that may not be consequences into separate domains [Lines 269 – 271] The PRO instrument known at the time the clinical trials that can be clearly related to proposed can be developed for a variety of roles, are designed. If adverse effects are claims. including defining trial entry criteria, captured, PRO instruments should aim including excessive severity, evaluating to measure the adverse consequences treatment benefit, or monitoring of treatment separately from the adverse events. effectiveness of treatment. As with any clinical trial evaluating FDA-regulated medical products, all adverse events detected with a PRO instrument should be included in the clinical trial report. PRO Sponsors and CROs should include all [Lines 501-504] The FDA recognizes [Appendix Section V. Content Validity instrument validation transcripts, as detailed in that the validation of an instrument is Documentation.] Evidence that validation Appendix Section V and Appendix C - an ongoing process and that validity instrument captures all of the most Transcripts. relates to both the instrument itself clinically important concepts and items, and how it is used. Sponsors should and that items are complete, relevant consider a PRO [or ePRO] endpoint for (appropriate), and understandable evidence of content-related validity, to the patient. This evidence applies the instrument’s ability to measure the to both existing and newly created stated concepts, and the instrument’s instruments and is specific to the ability to predict future outcomes, as planned clinical trial population and illustrated in Table 4. indication.
  4. 4. 4The Difference between the FDA Draft Guidance and Final Guidance:How these modifications affect Sponsors and CROs Key Learnings Guidance for Industry (Final) Draft Guidance February 2006 for Sponsors and CROs December 2009 Enhanced Sponsors and CROs should follow the [Figure 1] The PRO Instrument [Section III.C., Figure 3] Development Wheel & Wheel & Spokes objectives and specific Development and Modification Process of a PRO Instrument: An Iterative Spokes action steps. provides general action steps did Process includes 5 objectives with diagram not include specific details about the specific action steps: (i.) Hypothesize development process. Conceptual Framework, (ii.) Adjust Conceptual Framework and Draft Instrument, (iii.) Confirm Conceptual Framework and Assess Other Measurement Properties, (iv.) Collect, Analyze, and Interpret Data, (v.) Modify Instrument. Reasons for Sponsors and CROs are encouraged [Lines 590 – 670] The FDA intends to [Section III.C.] Table 1. Common changing to utilize ePRO for subsequent trial consider a modified instrument as a Reasons for Changing Items during PRO a PRO phases, since the reasons for moving different instrument from the original Instrument Development instrument to electronic data capture can be easily and will consider measurement demonstrated within these new table properties to be version-specific. The • Clarity or relevance… of reasons. FDA recommends additional validation to • Response range… support the development of a modified • Variability… PRO instrument when one or more of the • Reproducibility… following modifications occur. • Inter-item correlation… • Ability to detect change… 1. Revised Measurement Content… • Item discrimination… 2. Application to a New Population or • Redundancy… Condition… • Recall period… 3. Changed Item Content or Instrument Format… 4. Changed Mode of Administration… 5. Changed Culture or Language of Application… 6. Other Changes…
  5. 5. 5The Difference between the FDA Draft Guidance and Final Guidance:How these modifications affect Sponsors and CROs Key Learnings Guidance for Industry (Final) Draft Guidance February 2006 for Sponsors and CROs December 2009 5 criteria Sponsors and CROs can provide [Lines 1101-1109] Validation – [Section III.D.] Content validity is used to evidence of content validity from these The process of assessing a PRO the extent to which the instrument demonstrate sources, as outlined in the Appendix: instrument’s ability to measure measures the concept of interest. content a specific concept or collection of Content validity is supported by validity A. Literature review and concepts. This ability is described in evidence from qualitative studies documentation of expert input terms of the instrument’s measurement that the items and domains of an B. Qualitative study protocols, properties that are derived during the instrument are appropriate and interview guides, and summary validation process. At the conclusion comprehensive relative to its intended of results for focus group testing, of the process, a set of measurement measurement concept, population, open-ended patient interviews, properties is produced that are specific and use.. and cognitive interviews to the specific population and the C. Origin and derivation of items specific form and format of the PRO [Glossary] Content validity - with chronology of events for instrument tested. The validity process Evidence from qualitative research item generation, modification, involves: demonstrating that the instrument and finalization measures the concept of interest D. Qualitative study summary that • Identifying the concept to be including evidence that the items supports content validity for item measured and domains of an instrument are content, response options, recall • Assessing the content validity appropriate and comprehensive period and scoring (i.e., being sure the items in the relative to its intended measurement E. Summary of qualitative studies questionnaire cover the important concept, population, and use. Testing demonstrating how item pool aspects of the concept from the other measurement properties will not was generated, reduced, and patient perspective) replace or rectify problems with content finalized. • … validity. Proof of Sponsors and CROs should choose an [Lines 334 - 337] … If a patient diary [Section III.D.] … If a patient diary or data entry ePRO System that can prove data entry or some other form of unsupervised some other form of unsupervised data times times, prove what steps are taken to data entry is used, we plan to review entry is used, we plan to review the required ensure that patient entries are authentic the clinical trial protocol to determine clinical trial protocol to determine what and accurate; and include this proof in what measures are taken to ensure that steps are taken to ensure that patients the archive for reconstruction. patients make entries according to the make entries according to the clinical study design and not, for example, just trial design and not, for example, just before a clinic visit when their reports before a clinic visit when their reports will be collected. will be collected. Evaluating a Sponsors and CROs are required [Lines 176 -181] A new PRO instrument [Section III.F.] … When a PRO modified PRO to prove a modified instrument’s can be developed or an existing instrument is modified, sponsors instrument adequacy. instrument can be modified is sponsors generally should provide evidence determine that none is available, to confirm the new instrument’s adequate, or applicable to their adequacy. That is not to say that product development program. When every small change in application or considering an instrument that has format necessitates extensive studies been modified from the original, the to document the final version’s FDA generally plans to evaluate the measurement properties. Additional modified instrument just as it would a qualitative work may be adequate, new one. depending on the type of modification made…
  6. 6. 6The Difference between the FDA Draft Guidance and Final Guidance:How these modifications affect Sponsors and CROs Key Learnings Guidance for Industry (Final) Draft Guidance February 2006 for Sponsors and CROs December 2009 Concerns Sponsors and CROs should design [Lines 725 – 726] The importance [Section IV.A.1.] Open-label about questions that minimize the effects of of blinding can be determined, in clinical trials, where patients and unintentional possible unblinding, such as using part, by the characteristics of the PRO investigators are aware of assigned and response items that ask for current instrument used. therapy, are rarely adequate to intentional status, not giving patients access [Lines 729-731] Questions that ask support labeling claims based on unblinding to previous responses, and using for current status, or PRO instruments PRO instruments. instruments that include many items that ask many questions, are harder to To prevent influencing patient about the same concept. answer in a biased way when previous perspectives, PRO instruments answers are not available. administered during a clinic visit [Lines 735-738] There are certain should be administered before other situations, particularly in the clinical assessments or procedures. development of medical devices, If the treatment has obvious effects, where blinding is not feasible and such as adverse events, the clinical other situations where there is no trial may be at risk for unintentional reasonable control group (and therefore unblinding. no randomization). When a PRO Suspicion of inadvertent unblinding instrument appears useful in assessing can be a problematic review patient benefit in those situations, the consideration for the FDA when FDA encourages sponsors to confer with assessing PRO endpoints. Therefore, the appropriate review division. when PRO instruments are included in a clinical trial, we encourage sponsors to include a single item during or at the end of the trial to ask patients to identify the clinical trial arm in which they believe they participated. Missing data Sponsors and CROs should use PRO [Lines 765- 768] We recommend the [Section IV.A.2] The clinical trial from patient instrument administration techniques study protocol describe how missing protocol should describe how missing withdrawal to minimize unblinding. data will be handled in the analysis. It data will be handled in the analysis. could also establish a process by which Patients should remain in the clinical PRO measurement is ascertained before trial, even if they have discontinued or shortly after patient withdrawal treatment, and should continue to from treatment exposure due to lack of provide PRO data. The protocol should efficacy or toxicity. also establish a process by which PRO measurement is obtained before or shortly after patient withdrawal from treatment should early withdrawal be unpreventable.
  7. 7. 7The Difference between the FDA Draft Guidance and Final Guidance:How these modifications affect Sponsors and CROs Key Learnings Guidance for Industry (Final) Draft Guidance February 2006 for Sponsors and CROs December 2009 Design Sponsors and CROs should design [Lines 796- 798] The FDA recommends [Section IV.D] It is critical that the requirements protocols with the end in mind, a that the study protocol define the clinical trial protocol define the for multiple standard practice for PHT and the PHT study endpoint measures and the endpoint measures and the criteria endpoints PROVision Science Team. criteria for the statistical analysis and for the statistical analysis and interpretation of results, including a interpretation of results, including a clear specification of the conditions for specification of the conditions for a a positive study conclusion. positive study conclusion, because determination of these criteria and conditions after data are unblinded will not be credible. Sponsors should avoid separate consideration of PRO endpoints from the clinical trial’s primary objectives in terms of clinical trial design or data analysis. Sponsors also should avoid cherry picking or post hoc selective picking of PRO endpoint results for inclusion in proposed labeling. Interpreting Sponsors and CROs should define [Lines 474-475] The FDA generally [Section IV.E.] Planning for Clinical data beyond and develop the responder definition intends to review a PRO instrument Trial Interpretation Using a Responder statistical early in trial preparation, rather than for: reliability, validity, ability to detect Definition. Regardless of whether the significance describing the minimally important change, and interpretability (e.g., primary endpoint for the clinical trial difference. minimum important difference). is based on individual responses to [Lines 802-807] The FDA recommends treatment or the group response, that sponsors discuss with the it is usually useful to display appropriate review division how best individual responses, often using an to plan for the interpretation of study a priori responder definition (i.e. the findings. In some cases, the FDA may individual patient PRO score change request an a priori definition of the over a predetermined time period that minimum observed difference between should be interpreted as a treatment treatment group means (i.e., MID) that benefit.) The responder definition is will serve as a benchmark to interpret determined empirically and may vary by whether study findings are conclusive. target population or other clinical trial In other cases, the FDA may request design characteristics. Therefore, we an a priori definition of a treatment will evaluate an instrument’s responder responder that can be applied to definition in the context of each specific individual patient changes over time. clinical trial.
  8. 8. 8The Difference between the FDA Draft Guidance and Final Guidance:How these modifications affect Sponsors and CROs Key Learnings Guidance for Industry (Final) Draft Guidance February 2006 for Sponsors and CROs December 2009 Specific Sponsors and CROs should choose an [Lines 847-857] Sponsors should also [Section IV.F]… Sponsors also should concerns ePRO System that plan to avoid the following:9 avoid the following: about ePRO Instruments • Archives eSource data; • Direct PRO data transmission from • Direct PRO data transmission from • Documents all data changes with an the PRO data collection device to the the PRO data collection device to electronic audit trail; sponsor (i.e., the sponsor should not the sponsor, clinical investigator, • Provides database backup; have exclusive control of the source or other third party without an • Prevents eSource modifications document) electronic audit trail that documents except by Investigator or designated • The existence of only one database all changes to the data after it leaves site staff (not the Sponsor, not the without backup (i.e., risk of data the PRO data collection device. ePRO provider.) corruption or loss during the trial • Source document control by the • Ensures retention of any adverse with no way to reconstitute or verify sponsor exclusively. event data captured by the system; the data • Clinical investigator inability to • Prevents premature access to • Removal of investigator accountability maintain and confirm electronic PRO unblinded data; for confirming the accuracy of the data accuracy. The data maintained • Ensures timely transmission of data by the clinical investigator should important PRO safety data to the • Loss of adverse event data include an audit trail to capture clinical investigator responsible for • Access to unblinded data any changes made to the electronic the patient; and • Inability of an FDA inspector to PRO data at any point in time after • Enables full trial reconstruction inspect, verify, and copy the data at it leaves the patient’s electronic from archival records by an FDA the clinical site during an inspection device. investigator at each clinical site. • An insecure system that allows for • The existence of only one database easily alterable records. without backup (i.e., risk of data corruption or loss during the trial 9 The FDA specifically welcomes with no way to reconstitute or verify comment and additional information the data). that will inform these policies as new • Ability of any entity other than electronic PRO technology is developed the investigator (and/or site staff and used in the medical product designated by the investigator) to development setting. modify the source data. • Loss of adverse event data. • Premature or unplanned access to unblinded data. • Inability of an FDA investigator to inspect, verify, and copy the data at the clinical site during an inspection. • An insecure system where records are easily altered. • Direct PRO data transmission of important safety information to sponsors, clinical research organizations, and/or third parties, without ensuring the timely transmission of the data to the clinical investigator responsible for the patients.
  9. 9. 9The Difference between the FDA Draft Guidance and Final Guidance:How these modifications affect Sponsors and CROs Key Learnings Guidance for Industry (Final) Draft Guidance February 2006 for Sponsors and CROs December 2009 How to Sponsors and CROs should elicit PRO [Lines 109-119] Patients Provide a [Section V.E.] Because statistical demonstrate data to characterize the treatment Unique Perspective on Treatment significance can sometimes be treatment effect, and be prepared to explain the Effectiveness. PRO instruments achieved for small changes in PRO benefit mean improvements within different can be developed to measure what measures that may not be clinically patient subsets. patients want and expect from meaningful (i.e., do not indicate their treatment and what is most treatment benefit), we encourage important to them. When used to sponsors to avoid proposing measure study endpoints, PRO labeling claims based on statistical instruments can augment what is significance alone. known about the product based on To demonstrate treatment benefit, the clinician perspective or physiologic we find it informative to examine the measures. This is important because cumulative distribution function (CDF) improvements in clinical measures of responses between treatment groups of a condition may not necessarily to characterize the treatment effect correspond to improvements in how the and examine the possibility that the patient functions or feels… mean improvement reflects different responses in patient subsets… Proving that Protocol designers should use PRO [Lines 49-52] The term conceptual [Glossary] Conceptual framework the concept is instruments to measure treatment framework refers to how items are of a PRO instrument - an measurable, benefit, and should examine the results grouped according to subconcepts or explicit description or diagram and the in ways that reveal whether medical domains (e.g., the item walking without of the relationships between the instrument is therapies work best only for certain help may be grouped with another questionnaire or items in a PRO the measure individuals or subsets in the treatment item, walking with difficulty, within the instrument and the concepts measured. of the population. domain of ambulation, and ambulation The conceptual framework of a PRO concept. may be further grouped into the concept instrument evolves over the course of of physical activity. instrument development as empiric evidence is gathered to support item grouping and scores. We [FDA} review the alignment of the final conceptual framework with the clinical trial’s objectives, design, and analysis plan. Appendix as Sponsors and CROs should include all No dossier outline was provided. [Appendix] Information on a PRO PRO and ePRO relevant Appendix components within Instrument Reviewed by the FDA. The dossier their PRO dossier. following topics represent areas that should be addressed in PRO documents provided to the FDA for review.
  10. 10. 10The Difference between the FDA Draft Guidance and Final Guidance:How these modifications affect Sponsors and CROs Key Learnings Guidance for Industry (Final) Draft Guidance February 2006 for Sponsors and CROs December 2009 A proxy- Sponsors and CROs should elect [Lines 694 - 699 ] Over the course [Section III.G.] … We discourage proxy- reported observer-reported outcomes for of some clinical trials, it can be reported outcome measures for this outcome is patients who are not able respond for anticipated that patients may become population (i.e., reports by someone not a PRO themselves. too ill to complete a questionnaire who is not the patient responding or to respond to an interviewer. In as if that person were the patient). such cases, proxy reporting may For patients who cannot respond for help to prevent missing data. When themselves (e.g. infant patients), we this situation is anticipated, the FDA encourage observer reports that include encourages the inclusion of proxy only those events or behavior that can reports in parallel with patient self- be observed. For example, observers report from the beginning of the study cannot validly report an infant’s pain (i.e., even before the patient is no intensity but can report infant behavior longer able to answer independently) thought to be caused by pain. so that the relationship between the patient reports and the proxy reports can be assessed.PHT Corporation PHT Corporation Sàrl www.phtcorp.com500 Rutherford Avenue 2, chemin Louis-Hubert Copyright © 2010 PHT CorporationBoston, MA 02129 USA 1213 Petit-Lancy, Geneva, SwitzerlandToll-Free: 877.360.2901 Phone: 41.22.879.91.00

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