Primary endpoint

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The primary endpoint ( Latin: primus = "the first") is the primary (primary) goal of the study in clinical studies .

It is the general outcome of the study that will be assessed using a clinical trial protocol . The primary endpoint can be used to determine whether the measures applied (generally medical treatment) were successful. For example, the survival rate or the risk of relapse ( relapse ) can be defined as the primary endpoint. The study then compares these criteria in the treated group with those in the control group. The primary endpoints must be determined before starting the study. The achievement of the primary endpoint determines the success or failure of a study.

O'Neill defines the primary endpoint as:

"A clinical endpoint that provides evidence sufficient to fully characterize clinically the effect of a treatment in a manner that would support a regulatory claim for the treatment."

"Clinical endpoint that provides sufficient evidence to fully describe the clinical effect of a therapy in such a way that it meets the regulatory requirements for a therapy."

Determination of the primary endpoint

Before the start (a priori) of a clinical study, the primary endpoint is determined as the main objective of the study. It is important that the most "hard", that is, measurable and clearly defined criteria are defined. Hard criteria are, for example:

  • Remission (complete regression of all signs of the disease)
  • Relapse (recurrence of the disease)
  • Death within 30 days of the intervention
  • Time to a heart attack or death

“Soft” endpoints, such as quality of life or pain, are non-quantifiable variables. They are only suitable to a very limited extent for definition as the primary endpoint. They flow into the secondary endpoints if necessary .

The primary endpoint of a study can be determined together with the approving authority (e.g. the FDA ).

Surrogate marker

see also main article surrogate markers

Surrogate markers are laboratory parameters that can be measured on the patient. Examples of this are: the white blood cell count , blood pressure , bone density and much more. The values ​​of one or more surrogate markers can in principle also be selected as “hard” (because measurable) primary endpoints. In this special case, one speaks of a surrogate endpoint . However, they are not a direct measure of the clinical benefit or harm of the therapeutic intervention. In the past, there have been several studies with surrogate endpoints which led to fatally wrong conclusions and which in some cases had significantly negative effects on the patients treated later. A pharmacodynamic effect is not evidence of therapeutic effectiveness.

Examples of surrogate endpoints with - in some cases postulated - correlations are:

An example of an incorrectly set surrogate marker as the primary endpoint is the administration of beta- carotene to smokers for the prevention of lung cancer . Although the primary endpoint (increasing the decreased vitamin level) was achieved, the administration also led to an increase in lung cancer mortality .

Other endpoints

In addition to the primary endpoint, one or more secondary endpoints are usually set. Occasionally tertiary endpoints as well . With regard to the possible side effects of the measures, safety endpoints are also set to protect patients. Finally, a combined endpoint is a combination of several individual criteria, one or more of which must be achieved in order to be able to confirm a hypothesis.

Examples of primary endpoints

In a study on the treatment of recurrent / refractory chronic lymphocytic leukemia of the B-cell type (B-CLL), the primary endpoint was the response of the patients (remission rates) to the therapy. The secondary endpoints were progression-free survival , overall survival , and tolerability and safety of therapy.

The ASCOT study examined the prophylactic effect of the ACE inhibitor perindopril and the calcium channel blocker amlodipine in high blood pressure patients. The primary endpoint was “non-fatal myocardial infarction and fatal coronary artery disease ”. Secondary endpoints included “mortality for all causes of death, cardiovascular mortality, fatal and non-fatal stroke, and all cardiovascular events and interventions”. The tertiary endpoint was the "new manifestation of diabetes ".

Reaching the end point

If a patient reaches the primary endpoint of a study, that patient will be excluded from the study, as is also the term endpoint.
In many clinical studies, the primary endpoint is not met. However, this is not a statement regarding a possible ineffectiveness of the drug. The drug being tested may have been administered in the wrong dosage or formulation.

In some studies, the secondary endpoints are met but not the primary endpoint. The reverse can also happen.

Individual evidence

  1. ↑ a b c d e M. Wolbers: Statistical Methods in Clinical Research ( Memento from March 4, 2016 in the Internet Archive ) (PDF). Basel Institute for Clinical Epidemiology, University of Zurich, 2007, p. 33.
  2. ↑ a b National Cancer Institute: Dictionary of Cancer Terms: primary endpoint, accessed December 4, 2007.
  3. ↑ a b c d e K. Lechner: Requirements for IT in the development of new drugs (PDF; 1.0 MB). Medical university Vienna.
  4. ↑ RT O'Neill: Secondary endpoints cannot be validly analyzed if the primary endpoint does not demonstrate clear statistical significance. In: Contr. Clin. Trials. 18/1997, pp. 550-556, doi : 10.1016 / S0197-2456 (97) 00075-5 .
  5. ↑ A. Diekmann: Methods of Social Research. 2006, ISBN 3-531-14362-X , p. 74.
  6. ↑ Serono announces highly significant positive results of the comparative study of Rebif® with Avonex® in multiple sclerosis, on: chemie.de, May 10, 2001.
  7. ↑ M. Berger, I. Mühlhauser: Drug safety: The effectiveness of drugs must also be checked after approval. In: Deutsches Ärzteblatt. 97, edition 4/2000, p. A-154. (from New Engl J Med. 330, 1994, p. 1029 and 1996; 334, p. 1150)
  8. ↑ a b The ASCOT BPLA Study Results: A big step forward in the prevention of cardiovascular events in hypertensive patients ( Memento of 16 January 2013 Web archive archive.today ) on: presseportal.ch, 4th September, 2005.
  9. ↑ German CLL Study Group, CLL2K protocol synopsis.  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. Retrieved December 3, 2007.@1@ 2Template: Toter Link / dcllsg.web.med.uni-muenchen.de  

literature

See also