CLINICAL TRIALS OF

BIOTECHNOLOGY
PRODUCTS
INTRODUCTION
• Biotechnological products consist of: recombinant proteins, cell-based
products, gene therapy products, vaccines and monoclonal antibodies.

• These products are typically intended for use in managing and/or curing
untreatable diseases

• These biotechnological products include proteins, from humans, animals

and micro-organisms.

• There is a need to emphasise the identification and alleviation of potential

risks associated with biological products, such as immunogenicity,
tumorigenicity, infection, biodistribution and persistence.
Phases of Clinical
Trials
Case Studies
• Clinical Trial of H1-A1 Monoclonal Antibody trial:
• For the patients with gram-negative bacteremia followed to death or day 28,
there were 45 deaths among the 92 recipients of placebo (49%) and 32
deaths among the 105 recipients of HA-1A (30%, P = .014)”

• Several more patients on placebo than on HA-1A (17% vs. 10%) had received
inadequate antibiotics (mostly patients infected with resistant pseudomonas)

• In a follow up trial, patients treated with HA-1A experienced higher mortality

than did patients receiving the placebo.

• Shows the problem of multiplicity of analyses.

Case Study
• Clinical trial for Fibrinolytic Agents in Myocardial Infarction
• Study noted than a active-controlled trial was used as placebo-controlled trials were deemed outdated.

• compared two fibrinolytic agents, alteplase and reteplase, in terms of their efficacy and safety in patients
with AMI.

• The primary end point was a composite of death, reinfarction, or disabling stroke at 30 days. The trial found
no significant difference between the two groups in the primary end point (14.7% for alteplase vs. 14.5%
for reteplase, P = .54)

• However, there were some differences in the secondary end points, such as a lower rate of intracranial
hemorrhage in the reteplase group (0.8% vs. 1.1%, P = .01) and a higher rate of revascularization
procedures in the alteplase group (19.9% vs. 17.3%, P < .001).

• The choice of fibrinolytic agent should be based on the individual patient's risk-benefit profile and the
availability of the drugs
Case Study
• In 1999, a trial was underway at the Institute for Human Gene Therapy at the University of Pennsylvania to
investigate gene transfer of the ornithine transcarbamylase (OTC) gene.

• OTC deficiency is a rare, x-linked, metabolic disorder that in its severest forms is fatal early in life.

• In the study in question, adults with less severe disease (heterozygous women and less severely affected
men) had an adenoviral vector containing the OTC gene injected into a hepatic artery in a dose-escalation
trial designed to evaluate safety and gene expression.

• After receiving the highest dose to be tested, an 18-year-old man acutely developed a systemic
inflammatory response, including disseminated intravascular coagulation, hepatic failure, cerebral
dysfunction, and acute respiratory distress syndrome. He died a few days after treatment.

• The FDA issued notification of violations of several GCP regulations, including:

• subjects (including the young man who died) who did not meet eligibility criteria were enrolled and treated;
• adverse events, animal toxicities, and protocol and consent modifications were not reported appropriately to the
institutional review board or the FDA;
• the protocol was not followed in various regards;
• informed consent was inadequately documented; and there were deficiencies in standard operating procedures,
Challenges of Clinical Trials Registration with
Biotechnological Products

Biotechnological products are derived from living organisms and have applications in medicine, agriculture,
industry and other fields. Clinical trials with biotechnological products pose several challenges, such as:

The complexity and variability of the products, which may affect their quality, safety and efficacy.

The ethical and regulatory issues related to the use of genetically modified organisms, animal or human
tissues, or stem cells.

The potential environmental and social impacts of the products, such as biosafety, biodiversity and public
acceptance.

selecting end points, entry criteria, and concomitant medications