Paving the way for more targeted medicines

Targeted medicines have already had a dramatic effect on treatment for many patients, with advances in technology instrumental in helping to ensure they reach individuals that will benefit from them.

The revolutionary therapies target abnormal signaling pathways or biological processes underlying a disease, enabling treatment to be tailored to a patient’s genetic mutations or protein expression profiles.[i] 

They have improved the survival rate of patients with certain cancers, including HER2 positive breast cancer (trastuzumab/Herceptin) and myelogenous leukemia (Imantib/Glivec), with more areas in oncology, such as immunotherapy and personalized cancer vaccines, ripe for targeted therapies.[ii] [iii]

Computer-aided drug design, which is helping developers to enhance drug discovery, and the use of machine learning and artificial intelligence (AI) are further advancing the development of precision medicine.[iv] [v]

With a disease no longer defined purely by its pathology and anatomy but by its molecular signature, what once might have been a broad-brush diagnosis is becoming increasingly specific. For example, a patient previously told they had malignant melanoma would now be given a diagnosis based on the disease’s mutation, BRAF V600, MET, NRAS, ALK and NTRK1 among them.[vi]

There are potentially hundreds or thousands of genetically defined subtypes for each cancer, the dominant field for targeted therapies, making the accurate delivery of treatment even more critical.

Finding the right patient

Biomarkers and companion diagnostics (CDx) are at the forefront of technology connecting life-saving therapies with those who need them.

Biomarkers are a powerful weapon in the fight against chronic diseases, matching therapies with patients according to individual biological characteristics. In precision medicine, predictive biomarkers help identify the right patient for each therapy, as well as preventing the delivery of inappropriate treatment.[vii]

Clinical validation studies assessing a biomarker’s accuracy, specificity, reliability, reproducibility and predictive value seek to show an association between the biomarker and a given endpoint, as well as its overall therapeutic value.[viii] Biomarkers associated with specific cancer types have helped to personalize treatment plans, improve patient outcomes, and prevent ineffective or potentially harmful approaches.

A companion diagnostic is a test to detect a predictive biomarker.  The US Food and Drug Administration (FDA) defines a companion diagnostic as a medical device that provides essential information for the safe and effective use of a corresponding therapeutic product.[ix] It is also a valuable tool in identifying patients at greater risk of serious side effects and monitoring responses to treatments. 

Drug developers need to understand how a therapy works to determine the biomarkers that are relevant for efficacy. This, in turn, guides the development of a CDx that can identify those patients who would benefit from the therapy.[x]

Given how important this connection is for regulatory approval, as well as subsequent clinical trials, therapeutic and diagnostic companies often take a collaborative approach during the development phase.

The regulatory road

Regulators understand the urgent need of some patients for targeted therapies, balancing safety and efficacy concerns against patient acceptance of risk in the absence of other effective treatment. Conditional marketing authorization in the European Union and accelerated approval in the United States are just two of the mechanisms used to address the benefit-risk balance.

The hurdles for targeted therapies are myriad, however, and developers should make full use of available regulatory assistance from the outset. The FDA’s Office of Therapeutic Products encourages formal and informal meetings throughout the development process,[xi] while the European Medicines Agency (EMA) and national competent authorities (NCAs) offer guidance at any stage of development. The Committee for Medicinal Products for Human Use (CHMP) also provides scientific advice and protocol assistance.[xii]

A personalized approach to drug dosing and administration requires rigorous scientific evidence. Regulators may request extensive data on biomarker validation and patient selection criteria prior to approval and insist on long-term follow-up to support approval. Pharmaceutical companies are also increasingly being asked to justify dosing regimens based on comprehensive pharmacokinetic and pharmacodynamic data.[xiii]

There are different pathways for companion diagnostics, with Europe requiring developers to go through the In Vitro Diagnostic Regulation (IVDR) and conformity assessment by a notified body.[xiv] Similarly, the FDA encourages sponsors of the therapy and the CDx to meet with device and therapy divisions to ensure the plan will provide sufficient supporting data on safety and efficacy for both.[xv] The EMA has also released guidelines for obtaining regulatory input in the early stages of developing genetic biomarkers.[xvi]

Different regulatory frameworks around the world can also make it difficult to standardize manufacturing processes, particularly when balancing customization – such as with a highly individualized treatment – with standardization. In a bid to address what the FDA maintains is the need for more “mechanistic understanding, improved manufacturing capabilities and additional tools”, the agency established precision FDA, a portal that supports next generation sequencing technologies.[xvii]

Shifting the dial

The steps for successful development and approval of targeted medicines are complex and challenging, but the demand for precision medicine is pressing. Close collaboration between sponsors, researchers and regulatory authorities is essential to ensure therapies reach patients in desperate need of treatment.

Precision medicine is an exciting field that promises tailored treatment to individuals according to their genetic makeup, molecular profile and disease. When therapy developers and diagnostic teams work together, and engage early and often with regulators, they give patients the best possible chance to access potentially life-saving therapies.

About the author:

Dr. Christian K Schneider is a leading authority on advanced therapies and Head of Biopharma Excellence and Chief Medical Officer for Strategic Product Development Consulting at PharmaLex. He has broad global regulatory authority experience having served as chair of the European Medicines Agency’s (EMA) Committee for Advanced Therapies (CAT), and EMA’s Biosimilar Medicinal Products Working Party (BMWP), and was one of the key architects of the agency’s advanced therapies and biosimilars framework.

Disclaimer:

This information provided in this article does not constitute legal advice. PharmaLex GmbH and its parent, Cencora, Inc., strongly encourage readers to review available information related to the topics discussed herein and to rely on their own experience and expertise in making decisions related thereto.

[i] Amplifying gene expression with RNA-targeted therapeutics, Nature, May 2023. https://www.nature.com/articles/s41573-023-00704-7

[ii] How Herceptin is Thought to Work. https://www.herceptin.com/patient/metastatic-breast-cancer/about-herceptin/how-it-works.html#:~:text=Herceptin%20%E2%80%9Ctargets%E2%80%9D%20HER2%20receptors%20to,to%20destroy%20that%20cancer%20cell.

[iii] Cancer Research UK. https://www.cancerresearchuk.org/about-cancer/treatment/drugs/imatinib

[iv] Emerging Promise of Computational Techniques in Anti-Cancer Research: At a Glance, Bioengineering, Aug 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9332125/

[v] Emerging Promise of Computational Techniques in Anti-Cancer Research: At a Glance, Bioengineering, Aug 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9332125/

[vi] The role of gene fusions in melanocytic neoplasms, Journal of Cutaneous Pathology

[vii] Biomarkers: Promising and valuable tools towards diagnosis, prognosis and treatment of Covid-19 and other diseases, Heliyon, Feb 2023. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9884646/

[viii] Biomarker Discovery and Validation: Statistical Considerations, J Thorac Oncol., 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012218/

[ix] Companion diagnostics, FDA. https://www.fda.gov/medical-devices/in-vitro-diagnostics/companion-diagnostics

[x] Companion diagnostics, FDA. https://www.fda.gov/medical-devices/in-vitro-diagnostics/companion-diagnostics

[xi] Interactions with Office of Therapeutic Products, FDA. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/interactions-office-therapeutic-products

[xii] Scientific advice and protocol assistance, EMA. https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-advice-protocol-assistance

[xiii] A framework to guide dose & regimen strategy for clinical drug development, CPT Pharmacometrics Syst Pharmacol., 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592517/

[xiv] Notified Bodies, European Commission. https://health.ec.europa.eu/medical-devices-topics-interest/notified-bodies_en

[xv] Notified Bodies, European Commission. https://health.ec.europa.eu/medical-devices-topics-interest/notified-bodies_en

[xvi] Qualification of novel methodologies for drug development: guidance to applicants, EMA, 2014. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/qualification-novel-methodologies-drug-development-guidance-applicants_en.pdf

[xvii] https://precision.fda.gov/