Wednesday, February 27, 2013

COPD as a Syndrome

Typically, in medical journals, we don’t like to include a lot of formula or mathematical expressions in articles. However I recently read a paper where a mathematical expression is used to describe the COPD as a syndrome. It is a good use of mathematical expression in this case.

John J. Reilly “COPD and declining FEV1 – time to divide and conquer?” (NEJM 359:15: 1616-1618 OCT 2009)

“In fact, COPD in the singular is probably a misnomer. It is more appropriate to view COPD as a syndrome that encompasses a variety of obstructive diseases that share a common exposure but differ in terms of mechanism of disease and response to therapy. This concept is expressed in the mathematical notation

In which COPDn represents subgroups of COPD. As a reflection of this recognized heterogeneity, investigator have developed new classification systems, such as the BODE index, which evaluates the body-mass index, the degree of airflow obstruction and dyspnea, and exercise capacity to create a 10-point scale in which higher scores indicate a higher risk of death. In addition, investigators have attempted to define other homogeneous subgroups of patients with COPD. “

For many complicated diseases, when we have a better understanding about the disease, we will see that one specific disease may have many different manifestations or phenotypes – so called ‘heterogeneity’. When designing a clinical trial for a disease with heterogeneity, it may be difficult to show the treatment effect on the patient population as a whole. The drug may only be effective on one of many specific sub-populations. The difficult is usually in finding this specific sub-population. The newly issued FDA guidance “Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and
Biological Products” is attempting to address this issue. 

Thursday, February 14, 2013

Current Topics in Bioethics - A Free Seminar

Free Seminar on Current Topics in Bioethics By Sheila Mikhail, founder of Life Sciences Law (LSL)

The field of bioethics merges various aspects of several disciplines, including biology, medicine, politics, and law. The role of human subjects in the investigation of therapeutics gives rise to several concerns within the realm of bioethics, with such concerns increasing over time.

This presentation will provide an overview of several areas with respect to bioethics, including:

(1) ensuring the safety of study participants in human clinical trials as it relates to the process of obtaining and ensuring informed consent,

(2) the use of drugs that have not yet been approved by the FDA for patients who have no other treatment options available under compassion use principles,

(3) the ownership of biological samples isolated from patients, and

(4) the patentability of isolated gene sequences.


Saturday, February 02, 2013

Should Expected Clinical Outcomes of the Disease under Study, which are study endpoints, be reported as AEs/SAEs?

Generally not. The new IND safety reporting regulation and associated guidance state that study endpoints that are Serious Adverse Events (SAEs) (i.e., the study is evaluating whether the Investigational Medicinal Products reduces the rate of the SAE) do not require immediate reporting to the sponsor unless there is evidence suggesting a causal relationship between the drug and the event. For example, a death ordinarily would not require immediate reporting to the sponsor as an SAE under a trial designed to compare all-cause mortality in subjects receiving either drug treatment or a placebo. On the other hand, in the same trial with an all-cause mortality endpoint, if the death occurred as a result of an anaphylactic reaction that coincided with initial exposure to the drug, or as a result of fatal hepatic necrosis, the death must be immediately reported to the sponsor as a SAE

Study endpoint information should be collected, tracked, and monitored, usually by a data monitoring committee, during the course of the study. The sponsor must report study endpoints to the FDA according to the protocol and not as IND safety reports, except in unusual cases as described above.

Some protocols instruct investigators to record and report all untoward events that occur during a study as AEs/SAEs, which could include common symptoms of the disease under study and/or other expected clinical outcomes that are not study endpoints. This approach enables frequency comparisons of all events between treatment groups, but can make event recording in the CRF burdensome, result in more expedited reports from investigators to sponsor, and fill safety databases with many untoward events that most likely have no relationship to study treatment and that could obscure signal identification.

In practice, some companies take the conservative approach and report the underlying disease symptoms / outcomes as the adverse events or serious adverse events. To report all  underlying disease symptoms / outcomes as adverse events is overkill and the symptom worsening could just be the lack of efficacy for the study drug. It may be reasonable not to report the underlying disease symptoms / outcomes as adverse events, but if the underlying disease symptoms / outcomes result in the consequences that meet the criteria for serious adverse event (see the SAE criteria in ICH E2D or EMA document ICH topic E2 A), the underlying disease symptoms / outcomes should be reported as AE and SAE. This seems to be the approach that a lot of pharmaceutical companies are taking.

In a clinical trial with tiotropoim in COPD patients, Boehringer-Ingelheim reported the most commonly serious adverse events as the following:
“COPD exacerbations were the most commonly reported serious adverse events. The incidence of COPD exacerbations reported as SAEs was lower in the Tiotropium group compared to placebo group (4.2% vs. 6.7% of patients, respectively).”
COPD exacerbation is underlying disease symptom and efficacy measure of the COPD, but if COPD exacerbation requires the hospitalization (also meet the severe exacerbation definition), the COPD exacerbation would need to be reported as SAE even though the mild / moderate COPD exacerbation may not be reported as adverse event.

For a clinical trial with thrombolytic agents such as tPA, any bleeding event should be reported as AE. However, in trials in Hemophilia patients, the bleeding event is the manifestation for the underlying disease (hemophilia A). The bleed event should not be reported as AE unless it meet the SAE criteria in which case, the bleeding event should be reported as SAE.  Bleeding would also be included in the efficacy assessment.  It would be appropriate to specify in the study protocol what should be and what should not be reported. The following language would be adequate in Hemophilia trials.
“Spontaneous and trauma-related bleeding episodes are expected as usual events in subjects with severe Hemophilia A. Thus, bleeding episodes need not be reported as adverse events unless severe enough to be classified as a serious adverse events. “
 In the summary of approval document for ADVATE, the bleeding event (Hematoma)  is reported as serious and drug related adverse event.

The worst situation is that the rule for reporting is not explicitly specified in the study protocol and different investigational sites take different approaches (at investigator’s discretion) in reporting the AE/SAE for underline disease symptoms / outcomes. In this situation, data are inconsistent across different sites.