This post is by Harmanpreet Harmanpreet, who interned with CCRM Australia. The CCRM Australia Training Program seeks to facilitate training for the future workforce of the Australian regenerative medicine sector and includes an internship program that accepts undergraduate and postgraduate students from Australia’s universities.
Approximately 25 per cent of late-phase clinical trials fail due to commercial and strategic issues. For example, the development team within a company developing a medical product, device or technology may make certain assumptions about how the product should function, only to find out later that the previously made assumption has caused the end product to miss customers’ expectations or needs. This could result in an ineffective use of time and resources and, in a worst-case scenario, result in failure of the product from both a medical and commercial standpoint.
A misconception is that innovation is a linear and sequential process from bench to bedside, passing from one development phase or team to another. In reality, it is an iterative process once translational activities begin, which makes it even more imperative to have clear goals. To avoid the risk of getting bogged down by the chaos, many translational and commercialization efforts have turned towards the target product profile (TPP) as an effective way to implement this iterative approach from bedside to bench and translation.
A TPP outlines the desired profile or characteristics of a target product developed to treat a particular disease or medical condition to ensure effectiveness in bench to bedside translation. The basic TPP template defines key elements of a therapy’s intended clinical use, including patient inclusion/exclusion criteria, the method and timing of treatment administration, dose, potential safety concerns, and the product’s expected mechanism of action, to name a few. The TPP captures more than clinical information to include manufacturing and supply chain considerations, thus increasing the orientation towards chemistry, manufacturing and controls (CMC). This concept was developed in 1997 by a Clinical Development Working Group composed of U.S. Food and Drug Administration (FDA) representatives and pharmaceutical sponsors to focus discussions and aid in understanding between FDA and the sponsors. (2)
The TPP’s benefits can be seen in the following contexts:
- In the industry context, in-house TPPs are used as planning tools that guide development towards desired characteristics or to identify projects that have strong clinical and commercialization feasibility. TPPs set R&D targets for funders and developers, minimizing the risk of late-stage drug development failure, increasing the probability that optimal safety and efficacy data are available in a timely manner, and saving the FDA meetings.
- In the regulatory context, TPPs are used as tools to frame development in relation to submission of product dossiers. Reflecting upon the FDA’s perspective, TPP embodies the notion of beginning with the goal in mind, requiring sponsors to plan for activities and documents to support product labelling concepts. The TPP template assists in constructive dialogues with the FDA, especially at pre-new drug application (pre-NDA) and pre-biologics license application (pre-BLA) meetings as the template captures the essence of the regulator’s concerns. The template can be used to capture constructive feedback, follow up actions and agreements/understandings arising from the conversation between the regulator and sponsor, all of which are critical for successful drug development and pathway towards marketing approval.
Focusing again on effective bench to bedside translation, building quality into the process design is a phrase commonly used, as is the term Quality by Design. Quality by Design is a systematic approach to product and process development that aims to enhance the assurance of safe and effective drug supply, and at the same time significantly improve manufacturing quality performance. The formulation of a TPP, more specifically Quality Target Product Profile (QTPP), is the first step of this approach to outline the quality, safety and efficacy of the product. It guides process development to achieve a product that is free from contamination, ensuring pharmaceutical quality and consistently reproducing the therapeutic benefit. The QTPP is an expansion of the TPP. For example, TPP defines dosage forms, whereas QTPP includes attributes of concentration, colour and clarity. There are many variations of a TPP and some are suited to regenerative medicine.
In 2015, the University of York developed a TPP for a CAR T-cell therapy, which is reproduced below as an example.
| Intervention | CD19 CAR T-cell therapies |
| Indication | Patients with B-cell acute lymphoblastic leukaemia (B-ALL) who have relapsed (with no further planned curative chemotherapy or haematopoietic stem cell transplant (HSCT)) or who are refractory to standard chemotherapy |
| Subgroups | Sources of heterogeneity such as relapsed/refractory status, previous HSCT, CAR design, dose, conditioning chemotherapy, tumour burden at the time of therapy, or age of the patients may be explored |
| Comparators | Best supportive care (e.g. salvage chemotherapy) |
| Efficacy outcomes | Response criteria such as complete response/remission (CR), partial response/remission (PR), and minimal residual disease negative (MRD); overall survival (OS); progression and/or event-free survival; persistence of CAR T cells; health-related quality of life; rates of HSCT |
| Adverse event outcomes | Cytokine release syndrome (CRS), B-cell aplasia, febrile neutropenia, neurologic effects |
(1)
Here is another TPP example for pain associated with diabetic neuropathy, below. The table defines the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed therapy development effort, such as disease indication, patient population (with details such as symptomatic or pre-symptomatic patients for some genetic diseases), delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy. A more robustly developed TPP sets goals that result in a superior Health Technology Assessment and the minimal acceptable level to be competitive. Doing so helps build a stronger business case, supports planning and decision-making (e.g. milestone planning, clinical trial designs and business plans).
(Click here for the original source.)
In summary, the TPP is a valuable tool for drug development which not only guides the clinical development decision, but also the foundation for marketing success. It also contributes to the ultimate goal of driving greater efficiencies and shorter timelines to the approval of an optimally marketable and profitable product.
(Ed: If you enjoyed this post, you may also find The Canadian regulatory system for cell and gene therapies to be an interesting read. I also recommend CCRM’s CDMO Education Centre blogs. It’s a hub that provides valuable technical information and resources to support efforts to manufacture cell and gene therapies.)
Reference:
- [PDF] Research Protocol Exploring the assessment and appraisal of regenerative medicines and cell therapy products – Free Download PDF [Internet]. Silo.tips. 2015 [cited 11 October 2020]. Available from: https://silo.tips/download/research-protocol-exploring-the-assessment-and-appraisal-of-regenerative-medicin
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