Risk Management Program and Biologics

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By John Leombruno

The traditional method of identifying the potential toxicity of small molecule pharmaceuticals is quite exhaustive and consists of several investigations required by regulatory agencies, including in-vitro assays, multispecies animal toxicity studies, single dose safety/pharmacokinetic studies in healthy volunteers, short term multiple dose safety and efficacy studies in diseased subjects, reproductive toxicity studies, genotoxicity studies, carcinogenicity studies, etc.

In the past, these methods have worked relatively well in helping researchers identify the risk:benefit ratio for products during its development.
In recent years the pharmaceutical industry has taken advantage of advances in biotechnology and has invested billions into the research and development of therapeutic biologics. Often therapeutic biologics are incredibly selective for its intended target, this selectivity may mean that a biologic may be highly active in humans but inactive in animals typically used for pre-clinical testing.

An example of this includes the anti-tumour necrosis factor (TNF) medication infliximab. Infliximab binds to and inactivates human TNF, however, it does not affect TNF in several common laboratory species such as rhesus cynomolgous, pigtail macaque, cotton-top tamarin, baboon, marmoset, pig, rabbit, rat and the mouse3, therefore, the insight into the risk:benefit ratio of biotherapeutics provided by animal models may be limited. The testing of human specific biotherapeutics in animal modes often requires the use of transgenic animals that express the human form of the target protein. Unfortunately, the human protein may not interact with the animal’s immune system in the same manner as the native protein and may affect the pathogenesis of disease in the animal in unknown ways.

Another method of testing a human specific biotherapeutic in animals is to use an animal specific biotherapeutic with a similar mode of action, in other words, instead of testing an antibody to human-TNF in a mouse the researchers test an antibody to mouse-TNF in the mouse. This indirect approach offers minimal insight into the potential toxicity and activity of the human specific version since the different portions of a therapeutic biologic molecule, such as the Fc region of an immunoglobulin or the epitope binding site, may interact in a species specific manner with the immune system and confer different or multi functionality. A well developed example of how the structure of an antibody can affect outcome is the myriad of antibodies that have been developed against CD4. While all the antibodies developed were able to bind to CD4 only half of the agents displayed activity in rheumatoid arthritis, additionally, the toxicity profiles were quite different across agents. The various anti-CD4 development programs demonstrate that even when targeting the same molecule biologics can have distinct toxic and therapeutic effects.

Together, these difficulties create challenges for the pharmaceutical industry in defining the risk:benefit ratio for biologics and in bringing biologics to market in manner that maximizes benefit and minimizes risk. This article will attempt to provide the reader with an introduction to risk minimization plans with a focus on the Phase III, pre-marketing and post marketing stages of a biotherapeutic’s lifecycle.

Pre-Marketing
The clinical research departments of Canadian pharmaceutical subsidiaries often become involved in clinical research in Phase II or III. Often the goals of the Canadian organization are to maximize the number of Canadian investigational sites in order to improve exposure and familiarity of the agents, involve prominent physicians and to meet enrolment targets in a timely manner. Unfortunately, risk management is not often a priority in this context. Local risk management efforts should consider both local clinical safety and efficacy risks. Local clinical safety risks include any local medical issue that increases the likelihood of adverse events in a specific region; an example may be local background rates of diseases, such as tuberculosis or histoplasmosis. Clearly, if a biologic can increase the risk for reactivating latent tuberculosis researchers may wish to add additional caution in areas with high latent tuberculosis rates.

Local efficacy risk is a similar concept, however, it focuses on factors that may alter the efficacy profile in a specific area. An example of local efficacy risk may arise due to the differences in genetics, health care, nutrition and other epidemiological factors. An example includes erythropoietin therapy in dialysis patients, several reports describe a reduced efficacy of erythropoietin in patients with thalassemia1, thalassaemia has a high prevalence in Mediterranean countries and Africa, therefore clinical studies evaluating the efficacy of erythropoietin therapy in dialysis patients should consider this efficacy risk.

It is acknowledged that in the Phase II and III stages of clinical research identifying local safety and efficacy risks is difficult, information on local issues can be investigated through the local medical literature, local registries and through pharmacoepidemiological analysis of local administrative datasets.
Perhaps the most important aspect of risk minimization in the pre-marketing stage is the meticulous analysis of all available datasets and information to ensure that pre-marketing pharmacovigilance efforts have identified and quantified the risks and benefits of the biotherapeutic as well as possible. The pre-marketing assessment will define the nature and the extent of the risk management plan to be implemented during the marketing of the biotherapeutic.

Post Marketing
A Risk Management Plan (RiskMAP) is a strategic safety program designed to meet specific goals and objectives in minimizing the known risks of a biologic while preserving its benefits. A properly designed and executed RiskMAP will target specific safety-related health outcomes using appropriate tools to achieve the objective. RiskMAP tools can be classified into four categories; pharmacovigilance, targeted education and outreach, reminder systems and performance-linked access systems, these tools are described in Table 1.

The appropriate selection of RiskMAP tools will be dependent on several clinical factors, including but not limited to the severity of the disease, the short and
long-term outcome disease and the probability and magnitude of adverse events. There are no regulatory guidelines on which tools need to be used in which situations often the final RiskMAP strategy is a result of negotiations between the sponsor and the regulator. Sponsers should seek to engage the regulator early in the RiskMAP design process, sponsors should consider the following:

The tools should minimize the burden on the healthcare system while providing adequate risk minimization.
Identify the key stakeholders who have the capacity to minimize the product’s risks (such as physicians, pharmacists, pharmacies, nurses, patients, and third-party payers) and define the anticipated role of each group.

Seek input from the key stakeholders on the feasibility of implementing and accepting the RiskMAP tools in usual healthcare practices, disease conditions, or lifestyles, if possible. Identify other RiskMAPs that provide appropriate benchmarking.

After agreement with the regulators on the appropriate RiskMAP strategy and implementation sponsors should develop internal objectives. These objectives should be shared with all the product departments (i.e. medical, clinical, marketing, and sales) so that a culture of risk minimization permeates the brand. The sponsor should revisit the objectives and monitor outcomes regularly, results will provide insight on the need to modify the RiskMAP.

Conclusion
Quantifying the pre-marketing risk:benefit profile of a biotherapeutic is more challenging than for a small molecule therapeutic. Given this challenge, pharmaceutical companies should strive to be extra vigilant in its efforts in managing risk relative to the potential benefit for biotherapeutics. Risk management plans and strategies should be considered throughout the biotherapeutic development process and continued through the entire lifecycle.

References
1.     Lai K.N, Wong KC, Li PKT, Lui SF. Use of recombinant erythropoietin in thalassemic patients on dialysis. Am J Kidney Dis 1992; 14: 239-245.
2.     Guidance for Industry Development and Use of Risk Minimization Action Plans. FDA. March 2005.
3.     Strand V, Kimberly R, Isaacs JD. Biologic therapies in rheumatology: lessons learned, future directions. Nature Reviews 2007; 6:75-92.
4.     Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. FDA March 2005.

John Leombruno, is currently president, clinical and patient services, GMD PharmaSolutions as well as a consultant to the industry. He has responsibility for four GMD Departments; Clinical Research, Patient Programs, Market Access and Medical Clinic Infrastructure. Formally trained as a Pharmacist, Leombruno has earned an MBA and an MSc in Pharmacoeconomics and is in the later stages of his doctorial training in Pharmacoepidemiology. His key research interests include the design and analysis of clinical trials, the use of administrative databases, and statistical research into various data pooling methods for estimating drug safety. He has responsibility and experience in many areas of the pharmaceutical industry ranging from market access, medical information, pharmacovigilance, medical affairs and business development and has roles ranging from Manager, Market Access to Vice President, Medical Affairs. Leombruno has been intimately involved in the development and implantation of RiskMAPs in Canada and the U.S.