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The process of conducting clinical trials with plasma-derived products is essentially similar to that for any pharmaceutical product. However, trials with these products do present some different challenges in terms of trial design, patient recruitment, and clinical trial supplies.
The process of conducting clinical trials with plasma-derived products is essentially similar to that for any pharmaceutical product. However, trials with these products do present some different challenges in terms of trial design, patient recruitment, and clinical trial supplies. This article addresses these issues and describes the indications for use of plasma-derived products and the production process.
Before 1960, plasma was the only agent generally available for the treatment of some genetically inherited disorders such as hemophilia. Passive protection against a number of infectious diseases was achieved by injecting animal serum containing artificially induced antibodies. Now, human plasma-derived products are widely available for the treatment of a variety of conditions ranging from congenital deficiencies of coagulation factors to primary immunodeficiency and passive immunization. The plasma-derived products available generally fall into three categories: coagulation factors, immunoglobulins, and human albumin solutions, details of which are given in Table 1.1
Figure 1. Plasma fractionation pathways. (Modified from "Plasma, plasma products and indications for their use," in ABC of Transfusion, 3rd ed., 1998, Ch. 8, 40-44, by H. Cohen, P.B.A. Kernoff, B.B.T. Colvin. Reproduced by kind permission of BMJ Books.)
1. Coagulation factor concentrates. Coagulation factor concentrates are used predominantly to treat congenital coagulation factor deficiencies. These are rare disorders, the most well-known of these being deficiencies of factor VIII (hemophilia A) and factor IX (hemophilia B), although the most commonly inherited bleeding disorder is von Willebrand disease.2
2. Immunoglobulins. Nonspecific (normal) immunoglobulin contains antibodies to all the micro-organisms prevalent in the donor population. Intravenous immunoglobulin is used mainly to treat patients with primary immunodeficiency syndromes (PID), including congenital hypogammaglobulinemia, common variable and severe combined immunodeficiencies, secondary hypogammaglobulinemia in patients with chronic lymphocytic leukemia, and multiple myeloma with recurrent infections. Other licensed indications for nonspecific immunoglobulins are idiopathic thrombocytopenic purpura (ITP), allogeneic bone marrow transplantation, Kawasaki Disease, and Guillain-Barre syndrome. Nonspecific immunoglobulins have been used outside the licensed indications to treat other autoimmune diseases, e.g., multiple sclerosis.
Specific immunoglobulins are obtained from donors whose plasma contains selected high-titre IgG antibodies against a specific antigen, as a result of either previous infection or active immunization. Preparations are available for use in passive prophylaxis of varicella-zoster, tetanus, hepatitis B, and rabies. Anti-RhD immunoglobulin is used in the prevention of hemolytic disease of the newborn.
Table 1. Plasma-derived products; indications for use
3. Human albumin solutions. Human albumin solutions were developed in the United States during World War II to provide an alternative to blood or dried plasma for resuscitating military casualties.3 Since the availability of these early preparations, the purity of human albumin solutions is much improved, with a low incidence of adverse reactions. Human albumin solutions are currently used for the clinical management of: hypovolemic shock associated with blood loss, trauma, and surgical procedures; the clinical management of burn injuries; and fluid replacement regimens in therapeutic plasma exchange.
Fractionation of plasma into its different component parts was first developed by Edwin Cohn in 1944, and the modern manufacturing methods of plasma-derived products are based on his pioneering work. However, manufacturers continue to introduce new purification or viral inactivation/removal steps to further improve product safety. The plasma fractionation pathways are given in Figure 1.1
By virtue of the fact that plasma-derived products emanate from a substance taken from human beings, i.e., plasma, there is a risk of transmission of blood-borne viruses. In this context, there are two main types of viruses; lipid-enveloped viruses, e.g., human immunodeficiency virus (HIV) and hepatitis C virus (HCV), and nonlipid-enveloped viruses, e.g., hepatitis A virus (HAV) and parvovirus B19. Lipid-enveloped viruses are relatively easy to inactivate, whereas inactivation of nonlipid-enveloped viruses is more difficult. During the early 1980s, coagulation factor concentrates caused widespread transmission of HIV and non-A, non-B hepatitis (now recognized as mainly hepatitis C) with the result that manufacturers introduced steps to inactivate or remove these and other blood-borne viruses. Further outbreaks of HAV transmission in hemophiliacs in the early 1990s led to the Committee for Proprietary Medicinal Products (CPMP) to recommend that the manufacturing process should include a viral inactivation/removal step that is effective against nonlipid-enveloped viruses.4
Manufacturers now take measures to ensure minimum contamination of the starting plasma and to maximize elimination of blood-borne viruses and other infectious agents during the production process. In order to ensure minimum contamination of the starting plasma, manufacturers will ensure rigorous screening of donors and employ stringent tests for the presence of blood-borne viruses from donation and throughout the production process. During the manufacturing process, the plasma and process intermediates will be subjected to a variety of viral inactivation and removal procedures. Examples of these procedures include solvent/detergent treatment, which inactivates lipid-enveloped viruses, and viral filtration, which if the pore size of the filter is 15nm or less can remove small nonlipid-enveloped viruses such as parvovirus B19.
Given the modern manufacturing methods available, plasma-derived products have enjoyed an excellent safety record in recent years. However, there is still a risk that current viral inactivation/removal techniques may fail to eliminate all blood-borne viruses. Concern has arisen more recently that variant Creutzfeldt-Jakob disease (vCJD) may be transmitted by plasma-derived products. Abnormal prion proteins are thought to be the cause of vCJD, and although research appears promising, no test for the abnormal prion proteins is yet available. Importantly, however, to date there is no evidence of transmission of vCJD by plasma-derived products. Research suggests that the agent causing vCJD is unlikely to be carried through into the final product at levels capable of causing the disease. Although research for a test for the abnormal prion proteins appears encouraging, the availability of such a test does raise concern on the effect of donor numbers, as individuals may decline to donate fearing that the test suggests they may have a fatal disease, with a very long incubation period.5
Table 2. Adopted and Draft Guidelines for the Clinical Investigation of Plasma-derived Products as published by the CPMP (August 2003)
While one of the aims of the production process for plasma-derived products must be to inactivate or remove viruses, it is also essential to ensure that the biological function of the plasma protein is retained. Any change in a manufacturing procedure may alter the structure of the plasma protein and its activity, with the potential for patients to mount an immune response to the product they are being treated with.
Within the hemophilia population, the occurrence of an antibody against, for example, factor VIII, a so-called "inhibitor," is the most important treatment complication. Inhibitors occur in up to 30% of patients with severe hemophilia A, usually within the first 100 exposure days. Two inhibitor "outbreaks" occurred in the early 1990s in previously tolerant patients who had been treated for a number of years following exposure to plasma-derived products subjected to a modified virus inactivation method. Thus, the incidence of inhibitor formation may be affected by the specific product used for treatment and its potential to result in alteration of factor VIII molecules, "neoantigens."4 In addition to concern that the protein structure might be altered during the production process, manufacturers are also worried about the presence of trace proteins in products, because these might cause immunological reactions in patients. Therefore, manufacturers need to ensure that the biological function of the plasma protein is retained during the production process, and thereby the safety of the product is assured with respect to immunogenicity.
Collection of data addressing efficacy and safety with respect to immunogenicity, transmission of blood-borne viruses, and other adverse events is therefore essential in the design of clinical trials with plasma-derived products. These matters are equally important whether a clinical trial is being conducted on a newly developed product or on an existing product that has undergone a significant change in the manufacturing process.
Table 3. Number of patients to be studied for "new product" as recommended in the CPMP Notes for Guidance
The CPMP has published several Notes for Guidance on the clinical investigation of plasma-derived products. Draft Notes for Guidance are first discussed within the Blood Products Working Group and then released for consultation by the wider community of stakeholders before being finalized and adopted by the CPMP. Adopted guidelines are subject to regular revision.
The Notes for Guidance describe the information to be documented to demonstrate efficacy and safety when an application for marketing authorization is made. Typically, for a pharmaceutical product, the application for a marketing authorization would include data from several clinical trials in a Phase I–III program. The Notes for Guidance, however, describe a smaller number of studies on which data is to be submitted, which do not necessarily conform to a typical Phase I–III program.
Each of the Notes for Guidance is divided into two sections, "new products" and "modified products." The "new products" section relates to products not in a manufacturer's current portfolio for which a company is applying for marketing authorization. The "modified products" section relates to previously authorized products where a significant change in the manufacturing process has been made (e.g., additional viral inactivation/removal steps or new purification procedures). However, there is little difference in the clinical trials recommended for "new" and "modified" products. Details of the adopted and draft CPMP guidelines are given in Table 2.6
As previously stated, it is of paramount importance when designing clinical trials of plasma-derived products to collect data addressing the efficacy and safety with respect to immunogenicity, blood-borne virus transmission, and adverse events. These aspects are reflected in the Notes for Guidance published by the CPMP.
Interestingly, virtually all the clinical trials detailed in the Notes for Guidance are open and uncontrolled in design. Each Note for Guidance gives recommendations for assessment of the pharmacokinetics, efficacy, safety, and viral safety of the plasma-derived product and indication to be studied. For assessment of efficacy, the Notes for Guidance will typically recommend the provision of pharmacokinetic (PK) data including in-vivo half life, area under the curve (AUC), and clearance, in addition to other measurements, e.g., consumption of product and clinical response to treatment. Assessment of safety will include monitoring of adverse events and immunogenicity. Because of the rigorous selection and screening of donors and the use of viral inactivation/removal methods during the production process, the CPMP place less emphasis on monitoring viral infection markers than during the mid- to late-1990s.
However, the Notes for Guidance recommend that a pretreatment serum sample be taken from each patient included in the clinical trials and stored at –70Â°C for possible future testing. Manufacturers must also provide information with the marketing authorization submission on the selection and testing of the source material, the testing of the capacity of the production process to remove or inactivate viruses, and the testing of the product at appropriate stages of production.
With regard to the number of patients to be recruited, the Notes for Guidance clearly state the minimum number of patients to be studied and submitted for marketing authorization. Examples for some of the products and indications are given in Table 3.4, 7-8 The sample sizes are small, which is a reflection that patients suffering from the conditions to be studied are rare and therefore difficult to recruit.
For plasma-derived products where there are no CPMP guidelines available, or for indications not yet generally acceptable to the regulatory authorities, a more conventional program of statistically powered clinical trials will need to be conducted and submitted for marketing authorization.
The US Food and Drug Administration (FDA) does not publish guidelines in quite the same way as the CPMP, although it does offer guidance to individual manufacturers with regard to the clinical trial requirements for plasma-derived products. Although the trial design and sample size requirements may differ between FDA and the CPMP, the primary endpoints would be similar for the products and indications to be studied. An example would be for a clinical trial of intravenous immunoglobulins in primary immunodeficiency syndromes, both FDA and the CPMP would require clinical data on the infection rate, the number of adverse events, and the pharmacokinetics of the product.
Many plasma-derived products are used to treat patients with relatively rare genetically inherited disorders, and the target patient populations are therefore often small. Within the United Kingdom, there are approximately 5,000 individuals registered with hemophilia A and 1,100 registered with hemophilia B.9 Worldwide, there are estimated to be more than half a million people with hemophilia (prevalence varying from 105 to 160 per million of the male population).2 If one looks at the number of patients affected with primary immunodeficiency syndromes, there are approximately 5,000 affected patients within the United Kingdom.10 Given that the patient populations are often small, recruitment into a clinical trial of a plasma-derived product in one of these rare disorders can be a slow process. It is therefore usual to plan trials as multicenter studies, even when the sample size is small, e.g., 12 patients.
Treatment of patients is another consideration. For example, in the case of patients with hemophilia, the bleeds that these patients suffer will vary in frequency according to the severity of their disease. Bleeds can be treated either as they occur (on demand) or treatment can be given regularly to prevent bleeds occurring (prophylaxis). With treatment and proper care, people with hemophilia can live perfectly healthy lives. Without treatment, hemophilia can cause crippling pain, severe joint damage, and early death. However, only 25% of people with hemophilia in the world receive adequate treatment.11 In developed countries, where access to treatment is good, many of the patients targeted are treated continuously for their condition and may not be willing to switch from their current product to a different product undergoing clinical trial. This may not be such an issue if the product under trial offers a significant advantage over their current treatment. An example might be that the new product is of higher purity and improved safety. Another example might be if the study is conducted in a country where supply of product is limited and patients are offered treatment prophylactically under the trial protocol when their current treatment regimen may be on demand to treat major bleeds. Similar considerations would need to be given to patients recruited for other rare disorders, for example primary immunodeficiency syndromes. Access to product on completion of the clinical trial must be discussed with the clinicians at the initiation stage. It may be that product is offered to patients under the "particular patient" scheme, until the product receives a marketing authorization. Due to the fact that the CPMP guidelines describe open, uncontrolled trials, continuation of product is relatively straightforward, the most important issue being that sufficient product must be ensured.
By consenting to participate in a trial, patients may be asked to switch products, undergo lengthy pharmacokinetic assessments, have more frequent hospital visits, have more blood samples taken, and have to complete trial documentation, e.g., diary cards. In addition, due to the rarity of some of the conditions to be studied, some patients may have already participated in several clinical trials. Therefore, one is often relying on the goodwill and altruism of patients to participate to a greater extent than in most other trials.
Clinical trial supplies for plasma-derived products present some challenges, but in essence no more than for any other pharmaceutical product. Supplies must be planned well in advance, packed, and labelled appropriately and drug accountability records kept. The CPMP guidelines state that data from the use of three batches of product needs to be submitted, and this needs to be planned with the production team at the study design stage. Plasma-derived products generally have a production lead time of about five months. This lead-time is made up of a 60-day inventory hold between donation and the start of production and 12 to 14 weeks in the production process. This production lead-time therefore needs to be taken into account when planning a clinical trial. Other issues that need to be addressed during the planning stages are:
Essentially, the process of conducting clinical trials on plasma-derived products is the same as for any other pharmaceutical product, although some different challenges do present themselves in terms of clinical trial design, patient recruitment, and supply of product. As with all clinical trial programs, the data must satisfy the regulatory authority to which a marketing authorization is being made with respect to efficacy and safety of the product.
The major differences between plasma-derived and other pharmaceutical products are in two areas. First, by virtue of the fact that plasma-derived products are extracted from a substance taken from human beings, there is a risk of viral transmission. Secondly, because the plasma is subjected during the production process to stringent purification methods, there is a risk that the biological characteristics and activity of the component proteins may be altered. For these reasons it is essential to ensure that concerns with regard to transmission of blood-borne viruses, immunogenicity, and other adverse events, as well as efficacy of the product, are addressed when designing clinical trials for them. As a result, clinical trials on plasma-derived products pose their own particular issues, and each day brings a new challenge.
1. H. Cohen, P.B.A. Kernoff, B.B.T. Colvin, "Plasma, plasma products and indications for their use," in ABC of Transfusion, 3rd ed.(1998, Ch. 8, 1998, pp. 40–44).
2. P.H.B Bolton-Maggs and K.J. Pasi, "Haemophilias A and B," The Lancet, Vol. 361, 24 May, 2003.
3. B.L. McClelland, "Human albumin solution" in ABC of Transfusion, 3rd ed. (1998, Ch. 9, pp. 45–48).
4. Note for Guidance on the Clinical Investigation of Human Plasma Derived Factor VIII and IX Products. CPMP/BPWG/198/95 rev.1.
5. B.L. Evatt, A. Farrugia, A.D. Shapiro, J.T. Wilde. Haemophilia 2002: Emerging Risks of Treatment. Haemophilia 2002; 8: 221–29.
6. The European Agency for the Evaluation of Medicinal Products: published on the Web site www.emea.eu.int (accessed 14 August, 2003).
7. Note for Guidance on the Clinical Investigation of Human Normal Immunoglobulin for Intravenous Administration (IVIg). CPMP/BPWG/388/95 rev.1.
8. Note for Guidance on the Clinical Investigation of Human Normal Immunoglobulin for Subcutaneous and Intramuscular Use. EMEA/CPMP/BPWG/283/00.
9. UK Haemophilia Centre Doctors' organisation. Report on the Annual Returns for 1999. UKHCDO, 2002.
10. Information from the PiA (Primary Immunodeficiency Association).
11. World Federation of Hemophilia: published on the Web site www.wfh.org (accessed 10 June, 2003).
Kate Gillanders is clinical research manager, Bio Products Laboratory, Dagger Lane, Elstree, Herts WD6 3BX, United Kingdom, +(44) 20 8258 2562, fax +(44) 20 8258 2611, email: firstname.lastname@example.org, www.bpl.co.uk.