Conducting clinical trials for osteoarthritis: OMERACT III

Various rheumatological and non-rheumatological organizations (for example, EULAR, FDA, SADOA, ORS) have published recommendations on the design of osteoarthrosis research. At present, the recommendations of OMERACT III (Outcome Measures in Arthritis Clinical Trials) and recommendations of the ORS (Osteoarthritis Research Society) on the design and conduct of clinical trials for osteoarthritis are the most widespread.

Recommendations for the design of clinical studies of osteoarthritis (according to Bellamy N., 1995)

Recommendations	Index
EULAR 1	Severity index of knee and hip joint osteoarthritis (Leken) General assessment of the patient's condition by the researcher Pain on YOURS General assessment of the patient's condition by the patient himself Time of passage of a certain distance (with gonarthrosis - time of ascent to one flight of flights)
FDA 2	Swelling Redness of the skin above the joint Painful on palpation Pain at rest or during movements The volume of movements Time of passage of a certain distance or time of ascent to one flight of stairs Assessment of the patient's condition by the researcher on the day of the visit Assessment of patients with his condition on the day of visit
SADOA 3	YOUR Functional index (W0MAC or Leken) The Doyle Index Decreased joint mobility Time of passage of a certain distance or time of ascent to one flight of stairs Consumption of analgesics and / or NSAIDs The number of exacerbations over a certain period of time (especially the presence of effusion in the knee joint) General assessment of the effectiveness of treatment for patients General assessment of the effectiveness of treatment by the researcher The quality of life

Note. ¹ EULAR - European League Against Rheumatism. ² FDA - Food and Drug Administration. ³ SADOA - Slow Acting Drug in Osteoarthritis.

The main result of the first OMERACT conference (OMERACT I), which was held in 1992, was the development of recommendations for the conduct of clinical studies in rheumatoid arthritis. It was these recommendations that formed the basis for the later criteria for improving rheumatoid arthritis. During the next OMERACT II conference, the issues of measuring the toxicity of drugs used in the treatment of rheumatic diseases, assessing the quality of life of rheumatic patients, and questions of pharmacoeconomics were discussed. The third OMERACT conference (1996) ended with the development of recommendations for the conduct of clinical studies in osteoarthritis and osteoporosis.

From all that has been said above, it is clear that the OMERACT movement went beyond the study of rheumatoid arthritis, which was originally reflected in its name. Therefore, it was proposed to rename it to OMR (Outcome Measures in Rheumatology), and after osteoporosis was included in OMMSCT (Outcome Measures in Musculoskeletal Clinical Trials). Mainly because of the euphony of the first abbreviation, it was decided to leave the name OMERACT.

Even before the beginning of the conference, participants were asked to fill out questionnaires to determine indicators that could potentially serve as efficacy criteria for conducting clinical studies of osteoarthritis. Then another questionnaire was proposed, in which participants were asked to rank according to significance indicators depending on the location of osteoarthritis (knee, hip joint, hand joints and generalized osteoarthritis), from the class of drugs studied (symptomatic or modifying the cartilage structure), from the class of indicators (clinical , instrumental and biological markers). The second task was difficult, because only 15 completed questionnaires were returned to the conference secretariat.

Already during OMERACT III, the conference participants had to propose a list of indicators for inclusion in:

• the main list of effectiveness criteria (mandatory for clinical studies of the III phase of patients with osteoarthrosis of knee, hip joints, joints of the hands);
• additional list of performance criteria (ie, those that may be included in the main in the future);
• a list of criteria that will not be included either in the main or in the additional.

After the publication of the results of the voting, several important issues arose that demanded a solution:

1. Is generalized osteoarthritis separate from other forms of the disease object for clinical investigation? (Resolution - further generalized osteoarthritis is not considered as an object for clinical research).
2. Does the time of onset of action of the investigational drug substance determine the need for different performance criteria? (Resolution - the time of the onset of action determines more often when to investigate what to investigate).
3. Do studies of the effectiveness of "simple" analgesics and NSAIDs require different criteria? (Resolution - the groups of criteria are the same, and the methods for determining them can vary).
4. Should there be different efficacy criteria for symptom modifying drugs and structure modifying drugs? (Resolution - groups of indicators included in the main list should be the same).
5. It is assumed that biological markers in the future will be an important part of the protocol for the clinical study of osteoarthritis, but at present convincing evidence of the importance of biological markers in assessing the effectiveness of treatment of patients, as well as their prognostic value for osteoarthrosis is not enough.
6. It was recognized that none of the existing methods for assessing the quality of life demonstrated advantages over others. The importance of assessing the quality of life in conducting clinical trials with osteoarthritis was noted. (Resolution - do not include the assessment of the quality of life in the main list of effectiveness criteria, but recommend that it be used in phase III trials lasting at least 6 months, and in the next 3 years - 5 years, determine the role of the quality of life indicator in conducting clinical trials).
7. It was noted that it is not excluded that in the future, when testing the efficacy of newly developed drugs, the criteria that are not included in the main and supplementary lists are not excluded.
8. Is it necessary to include the "stiffness" symptom in any of the lists of performance criteria? Whether pain and stiffness belong to the same group of indicators; Do patients understand with osteoarthritis the very concept of "stiffness"; how existing methods can assess stiffness? (Resolution - to assess stiffness in patients with knee or hip osteoarthritis should use WOMAC or the Leken index).
9. The question of the informative value of the "general doctor's assessment" indicator during clinical trials in patients with osteoarthritis was discussed (a similar problem was discussed during OMERACT I with regard to rheumatoid arthritis); Despite the fact that only 52% of the conference participants supported inclusion in the main list of efficiency criteria, the indicator was not excluded.

Preferences of OMERACT III participants in compiling a list of efficacy criteria for Phase III clinical trials in patients with gonarthrosis, coxarthrosis, and osteoarthritis of the joints of the hands (according to Bellamy N. Et al., 1997)

Index	Number of voted "for" inclusion,%		Number of voted "against" inclusion in both lists,%	Total number of voters
	In the main list	To an additional list
Pain	100	0	0	75
Physical Function	97	1	1	76
Visualization*	92	7th	1	76
General assessment of patients	91	1	1	75
General evaluation by the doctor	52	21	27th	73
The quality of life	36	58	6th	69
Morning stiffness	14	61	25	72
Others **	13	69	19	16
Inflammation	8	70	22	74

Notes: "Standard radiography, after demonstrating advantages over radiography - other methods (MRI, ultrasound, etc.)." For example, tenderness in palpation, active and passive movements; number of exacerbations, biological markers.

When drawing up the list of criteria, it was decided to include not the indicators themselves, but their groups, leaving the final choice of the evaluation method for the researcher. More than 90% of the OMERACT III conference participants supported inclusion of the following indicators (or their groups) in the main list:

• pain,
• physical function,
• general assessment of patients,
• visualization methods (with a duration of 1 year or more as a criterion for the effectiveness and safety of drugs modifying the
  structure of the cartilage).

[1], [2], [3], [4], [5]