Introduction Rheumatoid arthritis (RA) is a form of arthritis that causes pain, swelling, stiffness and loss of function in your joints. It can affect any joint but is common in the wrist and fingers. More women than men get rheumatoid arthritis. It often starts between ages 25 and 55. You might have the disease for only a short time, or symptoms might come and go. The severe form can last a lifetime. Rheumatoid arthritis is different from osteoarthritis, the common arthritis that often comes with older age. RA can affect body parts besides joints, such as your eyes, mouth and lungs. A multitude of related and ever changing classifications exist. The overall term Rheumatism is of little importance in clinical trials. Other distinctions and terms relevant to clinical trials are: Axial Spondyloarthritis: RA is an autoimmune disease, which means the arthritis results from your immune system attacking your body's own tissues. No one knows what causes rheumatoid arthritis. Genes, environment and hormones might contribute. Treatments include medicine, lifestyle changes and surgery. These can slow or stop joint damage and reduce pain and swelling. Disease Description From NIAMS Rheumatoid arthritis is a disease that affects the joints. It causes pain, swelling, and stiffness. If one knee or hand has rheumatoid arthritis, usually the other does too. This disease often occurs in more than one joint and can affect any joint in the body. People with this disease may feel sick and tired, and they sometimes get fevers. Some people have this disease for only a few months or a year or two. Then it goes away without causing damage. Other people have times when the symptoms get worse (flares), and times when they get better (remissions). Others have a severe form of the disease that can last for many years or a lifetime. This form of the disease can cause serious joint damage. Anyone can get this disease, though it occurs more often in women. Rheumatoid arthritis often starts in middle age and is most common in older people. But children and young adults can also get it. Doctors don't know the exact cause of rheumatoid arthritis. They know that with this arthritis, a person's immune system attacks his or her own body tissues. Researchers are learning many things about why and how this happens. Things that may cause rheumatoid arthritis are:
Because of an increased risk of coronary atherosclerosis and associated morbidity and mortality in patients with RA, efforts to modify risk factors such as cigarette smoking, hyperlipidemia, hypertension, and sedentary life style should accompany treatment directed at RA." Rheumatoid arthritis can be hard to diagnose because:
To diagnose rheumatoid arthritis, doctors use medical history, physical exam, x rays, and lab tests. More details on Wikipedia: RA on Wikipedia Risk Factors for Rheumatoid Arthritis Agency Guidelines FDA In 1999 the FDA published a guidance for industry for clinical development programs for drugs, devices, and biological products for the treatment of RA. See FDA RA Guidance for Industry (1999). The guideline names new claims evaluated in clinical trials during drug development like reduction in the Signs and Symptoms of RA as measured for example by the ACR 20. The current guideline was issued in 1999. Due to scientific progress some of the examples in the guideline, especially with regards to biological activity may not be state of the art anymore. However, beside other sources this guideline is a good point to start digging deeper into RA trial methodology, especially for non-medics. Several new claims (A-F) for indications are described in detail, some of which include explicit recommendations for study designs, duration and outcome measures to support each claim. The following table summarises main points from section II of the guideline (II. New Claims For The Treatment Of RA). |
| Claim | Aim | Minimum Duration of Trial | Primary Outcome Measures | Primary Efficacy Evaluation | Explicit Study Design Recommendation from Description of Claim | Additional Consideration for Study Design |
| A. Reduction in the Signs and Symptoms of RA | demonstrate symptomatic benefits which are not only short-term | 6 months, 3 months if "well-characterised pharmacologic class" | Composite endpoints: e.g. Paulus criteria, ACR20; Signs/Symptoms: e.g. 66- or 28-joint count, Physician/Patient Global Assessment | response over time preferred over baseline to final observation | -- | products with potential to elicit antibody formation need to be assessed for durability |
| B. Major Clinical Response | demonstration of a continuous six-month period of success by the ACR 70 | at least 7 months for drugs expected to have rapid onset of action otherwise longer | ACR70 | statistically significant improvement in response rates by the continuous six-month ACR 70 definition | randomised, control group on background therapy | duration of 7 months should be confirmed upfront as this is the minimum duration |
| C. Complete Clinical Response | therapeutic benefit of greater magnitude than in B for a at least 6 months period. | depends on time to onset of drug effect, 1 year duration if rapid-onset | continuous six-month period of both remission by ACR criteria and radiographic arrest (no radiographic progression or modified Sharp methods) | categorical endpoint (patient complete response or treatment failure) as the primary outcome measure | duration of at least 1 year | Showing a benefit requiring ongoing drug therapy should be considered |
| D. Remission | remission by ACR criteria and radiographic arrest over 6 months while off all anti-rheumatic therapy | depends on time to onset of drug effect, 1 year duration if rapid-onset | continuous six-month period of both remission by ACR criteria and radiographic arrest (no radiographic progression or modified Sharp methods) while off all anti-rheumatic medication | categorical endpoint (patient complete response or treatment failure) as the primary outcome measure | -- | Remission is not intended to imply cure, and a remission claim could be granted even if patients relapse after six months or more of remission |
| E. Prevention of Disability | encourage long-term trials in RA | 2 - 5 years | HAQ, AIMS, general HR-QOL such as SF36 | no explicit advice for primary outcome, however, subjects should not worsen on HR-QOL measures over the duration of the trial. | improvement in signs and symptoms should have been demonstrated previously or improvement in signs and symptoms should be demonstrated concomitantly, more general HR-QOL measures (e.g. SF-36) should be collected | improvement in signs and symptoms should be demonstrated concomitantly |
| F. Prevention of Structural Damage | demonstrate prevention of structural damage | at least 1 year | X-Ray: Slowing of progression, prevention of new erosions; MRI/Ultrasonography | X-Ray: Comparison of films taken at one year (and subsequently) with baseline; categorical endpoint. Other techniques not well established. | All randomised subjects should be evaluated, handling of dropouts needs to be specified. It is expected that the drug has been shown to be effective in one of A-E. However, slowing radiographic progression is seen as surrogate marker | Pre-specification of handling of dropouts, logistics may be challenging. Sponsors who seek approval of a drug based on surrogate marker (21 CFR 314, subpart H and 21 CFR 601 subpart E) should definitely consult FDA staff to discuss clinical trial setup and methodology. |
While section II gives a general overview about what the aim of a study may be, section III (III. Considerations In RA Product Development) summarises important points to take into account during product development in RA. Many of the following topics are also covered by more general guidelines (e.g. ICH E9, Guidance for Statistical Analysis Plans). However, the FDA Guideline gives specific advice and points out frequently encountered issues in RA product development: Preclinical Considerations:
Pharmacokinetic/Pharmacodynamic Strategies:
Considerations in Phase II trials:
Efficacy Trial Considerations:
Analysis Issues:
Statistical Considerations in Efficacy Trial Design:
Safety Analysis:
Part IV. Special Considerations for Biological Products points out special characteristics and problems to consider for biologics. The information given in this chapter is far from being thorough but can give useful hints for those new to working with biologicals. The section lists common issues with biological such as:
Most of the content of the guideline also applies to development of medical devices. However, section V. Special Considerations for Medical Devices gives more detail regarding Efficacy and Safety Considerations. The last chapter, VI. Special Consideration for Juvenile Rheumatoid Arthritis, amends the previous sections with a definition of JRA, a detailed rationale for trials in this population, ethical considerations and additional information to be considered if a sponsor seeks approval for JRA. Outcome variables and claims are adjusted to fit this population and trial design issues, concurrent anti rheumatics agent administration as well as multicenter trials and center effects are discussed briefly. EMA In 2003 the EMA published points to consider on clinical investigation of medicinal products other than NSAIDs for treatment of Rheumatoid Arthritis. See EMA RA guideline (2003)- Compared to the FDA Guideline the respective EMA document is rather small (8 pages). It is a more recent document (2003), but as said before, examples and statements may be outdated meanwhile due to scientific progress. This possibility is clearly addressed in the introduction of the document, however, it is made clear that any claim based on further development of techniques “must show convincing evidence including validation and demonstration of clinical relevance”. The aim of the document “is to provide guidance with respect to the design of clinical studies related to therapeutic efficacy and clinical safety of anti-rheumatic therapy”. Therefore it clearly provides information necessary to setup clinical trials of later stages. To relieve painTo decrease inflammatory synovitisTo improve or sustain physical functionTo prevent structural damage This approach is different to the FDA guideline which covers almost all aims of the EMA guideline with the claim “Reduction in Signs and Symptoms” already. The tools to measure efficacy for signs and symptoms, however, are the same (e.g. 28-joint count, Physician/Patient Global Assessment, pain score, ESR, CRP, HAQ, radiographs). Other measures may be acceptable but need to be validated. Validated composite endpoints are to be used to document efficacy (DAS, Paulus, ACR,…) as additional primary or secondary endpoints. These need to be consistent with the single efficacy endpoints. The FDA guideline clearly allows composite endpoints as primary efficacy measure (e.g. ACR20 for claim Reduction in the Signs and Symptoms of RA). Compared to the numerous claims listed in the FDA guideline the EMA PtC does not give clear advice on long-term trials and definition of more ambitious outcomes like clinical response or remission of RA symptoms. Both guidelines mention the potential use of imaging techniques such as MRI, ultrasound and radiographs to examine structural joint damage. Comparison of radiographs taken before and after introducing the study drug is the only method mentioned in more detail in both documents. The actual procedure to perform X-rays, their evaluation and methods of statistical analysis need to be part of the trial protocol and should be agreed with the respective Agency before start of the study. Other techniques such as MRI or ultrasound were not seen as established methods at the time the documents were issued. The EMA guideline explicitly sees these methods as “supportive evidence for efficacy but only when the methods have been subjected to prior validation and their clinical relevance predefined”. Clinical Trial Endpoints: Several scales have been developed and validated to measure the improvement of RA in a clinical trial setting. These scales are used in research to determine eligibility to participate in a research trial or to assess severity and disease progression. Scales may also be used in clinical practice to identify and monitor problems or gauge clinical function and degree of progression. None of these single measures can serve as a “gold standard” for the assessment of patient status in RA. Therefore, in clinical trials a combination of the below mentioned measurements is performed. Dichotomous Measurement:
Continuous Measurement:
Patient Recorded Outcomes
Other:
Data Challenges: Concomitant Medication Often subjects need to take a combination of drugs from various classes to treat symptoms of RA such as pain and swelling:
Component Scores (ACR, DAS..) Clinical trials in RA often have to use component scores due to the lack of a single outcome measure. These scores are calculated using total scores from patient questionnaires (e.g. HAQ-DI, Patient Global Assessment of Pain), investigator assessments (e.g. tender/swollen joint counts, Physicians Assessment of Disease Activity) and lab results (e.g. CRP, ESR). In order to be able to calculate a component score, all components must be available. This can be challenging for a number of reasons:
Plain Radiographs: With regard to radiology usually joints are read at least from 2 readers. Whereby longer terms are reasonable. =>Complicat calculation rules, which has to handle these amount of data. =>radiographs are often not done on the visit itself i.e. the date for radiographs varying to other measurements. MRI/Radiographs Interim Calculations: The calculation to the one score which is going into the analysis is for these methods already complicated. Therefore interim results might be reasonable. =>What to do with these interim results - are they necessary to be kept - if yes, how? Data Collection: Is there a CDE project for data collection and sharing available? Check for more details. SDTM Data: State if there are special domains already available for this disease. Are there TA specific working groups on the CDISC page stated. Check If there is no standard given on the CDISC pages state how the disease specific information/primary measurements could be stored in the SDTM data. You might want to propose a naming convention. ADaM Data: State if there are special domains already available for this disease. Are there TA specific working groups on the CDISC page stated which also address ADaM standards. Check If there is no standard given on the CDISC pages state how the disease specific information/primary measurements could be stored in the ADaM data. You might want to propose a naming convention. |