Transformative Medicines Challenge FDA and Manufacturers

New gene therapies and combination products require innovative regulatory approaches.
Dec 01, 2017
Volume 30, Issue 12, pg 8–9

Advances in biomedical science transformed medicine in 2017, as seen in FDA approval of the first gene therapy that modifies human cells to treat and possibly cure a deadly disorder. Recent months have witnessed the emergence of truly breakthrough therapies, led by Novartis’ CAR-T therapy Kymriah (tisagenlecleucel) for patients with relapsed acute lymphoblastic leukemia; this approval was followed by Yescarta (axicabtagene ciloleucel) from Gilead Sciences and Kite Pharma for broader treatment of a similar lethal condition. Spark Therapeutics’ Luxturna (voretigene neparvovec) promises to cure a rare genetic eye disorder that causes blindness. FDA reports that some 40 companies are developing CAR-T technologies for multiple indications and that it is monitoring more than 600 active investigational new drug applications (INDs) related to gene and cellular therapies.

Biopharma researchers also are achieving success in developing oligonucleotide therapies, including antisense drugs and short interfering RNA treatments (siRNAs) that can modulate immune pathways. Safety issues derailed advances in this area some 20 years ago, but now better understanding of oligo chemistry and product characterization are driving research programs. FDA set the pace in approving Biogen’s Spinraza (nusinersen) in December 2016, a first treatment for spinal muscular atrophy, which is often fatal for infants. More controversial was FDA’s approval of Sarepta Therapeutics’ Exondys 51 (eteplirsen) to treat Duchenne muscular dystrophy, due to its reliance on an uncertain surrogate endpoint to demonstrate efficacy. 

Scientific advances in genome editing technology, such as CRISPR-Cas9, also expand possibilities for using gene editing techniques to correct disease-causing mutations. While systems that edit DNA are hard to reverse, changes from RNA-editing procedures disappear over time, which can be a plus, or a liability, depending on the situation. Although the long-term effects of these drugs are unknown, these initial successes have spurred optimism about further development of treatments for both rare and more prevalent serious conditions, particularly neurological diseases such as ALS, Alzheimer’s disease, and Huntington’s disease. 

CMC challenges

Better understanding of manufacturing, formulation, and pharmacology of these emerging products is important in advancing development beyond early testing stages. At a conference in October 2017 on oligonucleotide-based therapeutics sponsored by FDA and the Drug Information Association (DIA), experts explored strategies for tackling quality risk management, setting specifications, and assuring compliance with chemistry, manufacturing, and control (CMC) standards for experimental treatments. Presentations covered the importance of control strategies and the need to characterize and qualify impurities, including the use of platform data in assessing oligo impurities. 

Firoz Antia, director of technical development at Biogen, described the complexities of addressing CMC issues in developing Spinraza, citing challenges in establishing impurity controls for starting materials, achieving process consistency, and classifying critical vs. non-critical limits. Specifications for clinical batches had to be negotiated, along with strategies for gaining waivers from in-country testing requirements for limited clinical supplies. FDA approved Spinraza with a number of post-approval study and quality assessment commitments, including programs to re-evaluate drug substance method validation data and acceptance criteria, to re-examine impurity acceptance criteria based on data from commercial batches, and to conduct stability testing on drug product process validation batches. The company also may find it appropriate to tighten specification limits and may explore room temperature storage possibilities and a continuous manufacturing system for future production. 

These challenges were echoed by Vidhya Gopalakrishnan, senior vice-president at Quark Pharmaceuticals, which has several oligo compounds in clinical trials. Development involves controlling for impurities in clinical supplies and establishing CMC strategies for global product development, he observed. And process scale-up further requires identification and qualification of thresholds and specifications.  

Combos crucial

The process of developing and delivering cutting-edge gene therapies also involves ensuring reliable and accurate delivery and dosing for patients, objectives that increasingly involve devising combination products that utilize prefilled syringes and autoinjectors for safe and accurate patient treatments. Biopharma manufacturers thus face additional challenges in working with device makers to devise, test, and produce reliable and efficient combination products, commented Bret Coldren, director of pharmaceutical development at Ionis Pharmaceuticals at the oligo conference. He emphasized the importance of establishing and evaluating device design controls early in drug development and of ensuring compatibility of the components, as drug viscosity may affect syringe design, and inhalation devices need to efficiently target a lung treatment. 

Provisions in the 21st Century Cures Act and in the FDA Reauthorization Act (FDARA) approved in August 2017 bolster FDA’s Office of Combination Products (OCP) and its role in advising on whether a new combination therapy should be designated as a drug, biologic, or device, key to determining which FDA center serves as the regulatory lead. OCP officials and other FDA staffers outlined the latest developments in this area at a DIA conference on combination products, also in October in Bethesda, MD, highlighting efforts to update existing guidances and to prepare additional advisories on labeling issues and bridging studies. 

A main OCP initiative is to provide more assistance to manufacturers, particularly those developing more complex cellular and gene therapies that seek to utilize auto injectors, metered dose inhalers, and nasal sprays. OCP receives hundreds of inquiries on issues related to product classification, many seeking early advice on the regulatory designation process. FDA officials emphasize the importance of achieving consistency throughout the agency in making timely decisions on combination product oversight to support the development and approval of innovative drug delivery approaches. 

Strategies for complying with good manufacturing practices (GMPs) are important in developing combination products, which face different rules on quality manufacturing for drug and device components. FDA has been working to explain and streamline the process for meeting manufacturing standards for both components, as seen in guidance that was finalized in January 2017 (1); further clarification of the process is due next year. FDA officials say they are open to considering alternative proposals from manufacturers for GMP compliance and advise firms to indicate clearly in submissions how multiple facilities aim to achieve standards. 

Another key issue for combination products is to understand and comply with human factor study requirements. Guynh Nhu Nguyes, associate director for human factors in the Division of Medication Error Prevention and Analysis in the Center for Drug Evaluation and Research (CDER), outlined at the oligonucleotides conference how human factors testing can ensure appropriate dosing and drug delivery and avoid medication errors and patient harm. FDA published a draft guidance in February 2016 on human factors studies for combination products (2) and is reviewing comments to finalize the policy. 

As FDA and industry continue to scope out regulatory pathways to bring critical new therapies to patients, they will be looking for strategies to address the high cost of gene and other breakthrough products that threaten to limit patient access to treatment. Current processes for developing and delivering complex new drugs are expensive and contribute to higher prices for these vital therapies. The situation puts a premium on efforts by FDA and biopharma companies to identify efficiencies and improved methods for testing and producing cutting-edge medical technologies. It also highlights the importance of strategies that encourage coverage and reimbursement for life-saving therapies by both public and private payers. 


1. FDA, Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products, Final Guidance (CDER, January 2017). 
2. FDA, Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development, Draft Guidance for Industry and FDA Staff (FDA, February 2016).   

Article Details

BioPharm International

Volume 30, Number 12

December 2017

Page: 8–9


When referring to this article, please cite it as J. Wechsler, “Transformative Medicines Challenge FDA and Manufacturers," BioPharm International 30 (12) 2017.

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