Monday, January 14, 2013

Non-interventional Clinical Studies

For interventional clinical trials, there are clear regulatory guidelines to govern the development of the study protocol, the conduct of the study, and the layout of the clinical study report. The requirements for clinical study protocol are specified in ICH E6 (Guideline for Good Clinical Practice) and for clinical study report are specified in ICH E3 (Structure and Contents of Clinical Study Reports).

However, there are also non-interventional clinical studies such as Post-Marketing Surveillance (PMS), Post Authorization Safety Study (PASS), Pharmacovigilence study, Pharmacoepidemiologic Study, Drug utilization study, Retrospective and Prospective registry studies. They are clinical studies because the patient information is collected from various clinical sites. They are non-interventional because the sponsor does not provide the study drug and provide no specific requirements how the patients should be treated. The regulatory guidelines for this type of non-interventional clinical studies can sometimes be vague and not as clear as those for clinical trials. The ICH guidelines that were developed for clinical trials may not all be applicable to this type of non-interventional clinical studies.

Post-Marketing Surveillance (PMS) studies are non-interventional, observational, post-authorization studies where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorization (i.e. no study medication). The assignment of the patient to a particular therapeutic strategy is not decided in advance by the trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data.

Post Authorization Safety Study (PASS) in EU: A post-authorization safety study (PASS) is defined in Directive 2001/83/EC (DIR) Art 1(15) as any study relating to an authorized medicinal product conducted with the aim of identifying, characterizing or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures.

Pharmacoepidemiology study: A pharmacoepidemiology study applies epidemiological methods to studies of the clinical use of drugs in populations. A modern definition of pharmacoepidemiology is: «the study of the use and effects/side-effects of drugs in large numbers of people with the purpose of supporting the rational and cost-effective use of drugs in the population thereby improving health outcomes».

Drug utilization research: drug utilization study was defined by WHO in 1977 as «the marketing, distribution, prescription, and use of drugs in a society, with special emphasis on the resulting medical, social and economic consequences». Since then, a number of other terms have come into use and it is important to understand the interrelationships of the different domains.

Pharmacovigilance are terms used to refer to the monitoring of drug safety, for example, by means of spontaneous adverse-effect reporting systems, case-control and cohort studies.

Retrospective Registry: A retrospective study uses information on events that have taken place in the past. In most cases some or most of the data has already been gathered and stored in the registry. However and also in most cases, new data, but always on past events, may have to be requested. The data collection is typically through the medical charter review

Non interventional prospective studiesNon interventional prospective studies are prospective studies which are set up to investigate events that will take place after the study has been initiated. Post-marketing surveillance study may fall into this category. The main and very important difference between a clinical trial and a non interventional prospective study is that the data collection or patient-participation in the non interventional study does not interfere with the choice of treatment, sample collection, procedures, and the treatment itself, which should entirely follow standard hospital practices. Typically a non interventional prospective study behaves like a “fly on the wall” and will aim to collect information on how different centres deal with the same problem or type of patient. A non interventional prospective protocol cannot in any way set up conditions modifying either the treatment of the patient or the number or type of investigations the patients needs to be subjected to. It excludes the possibility of determining which treatment protocol should be used, randomiation or other types of patient allocation to a specific treatment, specified sample collection schedules, or collection of additional samples not included in the center’s routine procedures.

In terms of the elements required for the study protocol and the study report, there are different guidelines than the clinical trials. For PASS study, EMA: Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies  should be followed for developing the study protocol and the study report. There are also recommendations on data collection, data quality, data analysis.

In the United States, the most relevant guidance is Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment and E2E Pharmacovigilance Planning which is mainly focusing on the post-marketing data collection on adverse events or adverse drug reactions.

The recent passed PDUFA V also emphasize the importance of pharmacovigilance:
 C. Conduct and support activities designed to modernize the process ofpharmacovigilance
1. Continued use of expanded database resources: A critical part of the
transformation of the drug safety program is maximizing the usefulness of
tools used for adverse event signal detection and risk assessment. Use of data
other than passive spontaneous reports, including population-based
epidemiological data and other types of observational data resources will
continue to enhance FDA’s capability to conduct targeted post-marketing
surveillance, evaluate class effects of drugs, and potentially conduct signal
detection using data resources other than reports from the Adverse Event
Reporting System (AERS).  FDA will continue training and development of
existing staff on the use of these resources, and develop the information
technology infrastructure needed to support access and analysis of data from
these resources.  

Sunday, January 06, 2013

Randomized Withdrawal Design

FDA recently issued its new guidance to industry “EnrichmentStrategies for Clinical Trials to Support Approval of Human Drugs andBiological Products”. The section D of the guidance detailed the Randomized Withdrawal Design as one of the enrichment strategies.

Randomized Withdrawal study design is not new and has been practically used in many drug trials and in NDA or BLA applications. Randomized Withdrawal study design is especially popular in CNS and neurology areas.

According to ICH ICH Topic E 10 “Choice of Control Group in Clinical Trials”, the Randomized Withdrawal design is defined as:
 “In a randomized withdrawal trial, subjects receiving a test  treatment for a specified time are randomly assigned to continued treatment with the test treatment or to placebo (i.e., withdrawal of active therapy).  Subjects for such a trial could be derived from an organized open single-arm study, from an existing clinical cohort (but usually with a protocol-specified "wash-in" phase to establish the initial on-therapy baseline), from the active arm of a controlled trial, or from one or both arms of  an active control trial.  Any difference that emerges between the group receiving continued treatment and the group randomized to placebo would demonstrate the effect of the active treatment.  The pre-randomization observation period on treatment can be of any length; this approach can therefore be used to study long-term persistence of effectiveness when long-term placebo treatment would not be acceptable.  The post-withdrawal observation period could be of fixed duration or could use early escape or time to event (e.g., relapse  of depression) approaches.  As with the early escape design, careful attention should be paid to procedures for monitoring patients and assessing study endpoints to ensure that patients failing on an assigned treatment are identified rapidly. 


In 2001, Nation Academies published a report “Small Clinical Trials: Issues and Challenges”. It stated the advantages and disadvantages of the Randomized Withdrawal Design:
 “The advantages of this study design are that individuals receiving the experimental intervention continue to do so only if they respond, whereas individuals receiving the placebo do so only until their symptoms return. Disadvantages include carryover effects, difficulties assessing whether the underlying disease process is still active, and long lag times to adverse events if the disease is in remission. This design is more appropriate in phase I and II trials involving healthy volunteers because it is less likely that effective treatments are being withdrawn from those who need it. In some studies, however, measurement of the placebo effect is essential (e.g., studies of drugs for the treatment of depression), and such studies might require the use of a randomized withdrawal design. In those cases, voluntary, informed consent is essential, as is the provision of care during the withdrawal period.”
Additional advantage of this design is to study the long-term efficacy or safety (withdrawal effect) and additional disadvantage is the longer overall study period (additional period is needed to identify responders).

Some of the practical cases of using the Randomized Withdrawal Design in clinical trial are:

  • Randomized withdrawal design used in the clinical trials for ADHD
  • Cystic Fibrosis-Dependent Exocrine Pancreatic Insufficiency trial used an open label period to establish the baseline for the randomized withdrawal period. The endpoint is the change from the baseline after the open label period to the end of the randomized withdrawal period
  • Flibanserin (a so-called Female Viagra drug) for the treatment of hypoactive sexual desire disorder (PSDD) in premenopausal women. One of the pivotal trials began with a 24-week open label phase, which then enrolled only “responders” into the randomized withdrawal phase
  • IGIV-C for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): the trial had two randomization. The second randomization was only for responders (to IGIV-C or Placebo) from initial (the first) randomized period. In extension period, the randomized withdrawal design was employed. The responders were re-randomized to IGIV-C or Placebo to study the long-term efficacy by comparing the relapse rates and the time to relapse. Notice that the responders from Placebo group in initial (first) randomized period were also included in the randomized withdrawal period. This is purely for maintaining the blinding.

 Additional Reference:     Enrichment Strategies Robert Temple, MD