Biopharma Seeks Balance
A biopharma company answers to multiple masters: the patient who depends on effective drug products for health or survival; regulatory authorities that monitor quality; and investors that demand financial performance. Maintaining a balance of multiple, sometimes conflicting priorities is no easy task for companies at any development stage.
During the past 30 years that BioPharm International covered the biopharma market, the industry continually evolved thanks to advances in biology, genomics, and other sciences. The strategic shift by small companies to focus on rare or orphan diseases that afflict smaller populations altered research and manufacturing processes and also changed business models. Big Pharma spinoffs, startups, virtual companies, industry-academia partnerships, and a growing contract services market contribute to the changing landscape of the pharmaceutical industry.
Globalization, the rise of China as a player in the pharmaceutical market, ongoing payor pressure, regulatory reform and initiatives, the biosimilar threat to innovator companies, and a fluctuating investment environment can upset the balancing act biopharma companies must perform.
While the business, economic, political, and regulatory perils may be difficult to predict, science and technology can give biopharma more control and predictability over drug development and manufacturing. There is much work to be done, however, experts say.
More science and technology
Drug companies must give more attention to understanding the science behind their potential therapy. To increase the potential for approval, companies need to provide better “packages” that describe how the drug works, said Scott Gottlieb, FDA commissioner, at the 2018 BIO convention in Boston on June 7, 2018. Applications that lack understanding of how the drug works can slow the review process.
Looking inward, FDA recently outlined plans to modernize drug review efforts at the agency to give scientists and physicians more time to focus on drug development and collaborations needed to ensure drugs are assessed properly. The initiatives include developing career paths for talented scientists; development of multidisciplinary teams from different offices of FDA’s Center for Drug Evaluation and Research (CDER) to work together on drug applications; centralized project management functions and processes within the Office of New Drugs; improved knowledge management; a unified post-market safety surveillance framework to monitor the benefits and risks of drugs before and after approval; and patient-focused drug development, wrote Janet Woodcock, director of CDER (1).
For established and emerging therapies, drug companies must improve process development and manufacturing functions to ensure drug quality, reduce the risk of manufacturing failure, and deliver drugs to market faster. “We should not be having so much trouble with manufacturing,” Woodcock said during an FDA Town Hall session at the 2018 BIO convention on June 5.
FDA actively encourages bio/pharma companies to embrace advanced manufacturing processes and incorporate newer technologies for established systems; however, the industry’s conservative approach to change—due primarily to budget restrictions and fears of regulatory delays—can result in aging equipment and facilities, quality failures, and drug shortages. Companies optimize a process to get approval and a drug on the market, said Woodcock, then stick with the same process for 30 years.
CDER’s Office of Pharmaceutical Quality has established an Emerging Technology Program to “promote the adoption of innovative approaches to pharmaceutical product design and manufacturing.” Biopharma and technology supplier representatives can meet with members of FDA’s Emerging Technology Team to discuss, identify, and resolve potential concerns about the use of a novel technology for drug manufacturing prior to filing a regulatory submission.
FDA reports that it has considered emerging technologies for biological molecules including controlled ice nucleation for lyophilization processes, predictive modeling for process monitoring and closed loop bioreactor control, next-generation sequencing, continuous manufacturing for downstream processes, and a manufacturing platform for continuous bioprocesses (2).
New challenges to manufacturing
Manufacturing processes have traditionally been established through lengthy development steps from laboratory scale, to pilot scale, to commercial scale; however, the emergence of personalized medicines reveals shortcomings of the traditional approach. The industry also is challenged by gaps in manufacturing scales from first-in-patient for commercial operations.
In the traditional model, process development progressed slowly as large, slow clinical trials progressed. FDA’s expedited approval process moves drugs to market faster, requiring developers to shorten the path from lab scale to production scale.
Moving from one technology process during scale up to another for manufacturing creates problems, noted Peter Marks, director of the Center for Biologics Evaluation and Research at FDA, to the audience at an FDA Town Hall session at BIO 2018. For emerging personalized therapies, the industry needs to bridge the gap from pilot to large-scale, patient-size manufacturing, he said.
Cost can be a big limiting factor. Investors are discouraged by the cost threat, so innovation is not sustainable, said Woodcock. If companies make pre-competitive advances on manufacturing processes, Marks noted, they can concentrate more resources on making a better drug.
There has been some progress to advance manufacturing processes through pre-competitive efforts. For example, industry groups championed efforts to address technical issues related to materials specifications and extractables and leachables, helping to accelerate the adoption of single-use systems, which can reduce turnaround times and cross-contamination threats.
New paradigm: Gene and cell therapies
FDA’s approval of the first cell and gene therapies in 2017 created new dynamics in the biopharma industry as well as new science, technology, business, and ethical questions. Now that personalized therapies have arrived, the biopharma industry must adopt new development processes, delivery methods, processing steps, and pricing schemes, and expand patient and physician education.
Gene therapies offer the potential to cure disease but there are risks, Gottlieb warned the audience at BIO 2018. For gene therapies, he said, 80% of the regulatory focus will be on product development issues and 20% on clinical issues.
With development and manufacturing playing such a crucial role, production challenges and high costs are recognized as roadblocks to the adoption of new therapies. Although costly, gene therapies can be manufactured on a small scale for limited patient populations with rare diseases. The high cost of making adenoviral vectors (AVV), however, will limit the use of such therapies to treat large populations of patients with common diseases. Developing sufficient quantities of a gene therapy for thousands of patients in a clinical trial would be cost-prohibitive, said Marks. Manufacturing processes need to be more productive for biopharma to consider these therapies for treating conditions such as heart disease or arthritis.
During a panel discussion, Delivering on the Promise of Gene Therapy, at BIO 2018, biopharma experts discussed strategies to improve the production of AVVs. Suggested methods included the use of a single platform to scale up production from R&D to pilot to commercial scale, and embedding a pilot laboratory with a contract manufacturer to get to GMP-quality production quickly. The panelists noted that analytics will be a key element in development and manufacturing phases and new potency assays are needed.
Regulatory authorities also need to get up to speed. The methods FDA uses to regulate gene and cell therapies will evolve, Marks said, and Gottlieb noted that FDA will produce guidance documents for gene therapy in 2018.
A fine balance
For patients needing unapproved treatments, any wait can seem too long; some are willing to take any risk. The Right to Try Act, enacted in May 2018, gives terminally ill patients access to therapies that have passed Phase I safety trials, but have not been approved by FDA. The legislation has been criticized as being duplicative of similar laws in individual states, potentially causing unknown harm, conflicting with scientific goals of clinical trials, and undermining the regulatory authority of FDA.
At the same time, FDA is facing criticism that it is approving drugs too quickly. A June 26, 2018 article (3) in ProPublica argued that while FDA is approving more drugs and at a faster pace, the expedited approach involves more risk for patients because approvals are based on limited information about safety or effectiveness from shorter clinical trials, not survival rates or cures.
With a business driven by scientific concepts that the general public may not understand, those working in the biopharma industry must strive to dispel myths about the underlying biology, ensure patient and payer understanding, share knowledge to develop cost-effective processes, and earn the trust of investors, regulators, and the public.
1. J. Woodcock, “FDA Proposes Process Modernization to Support New Drug Development,” FDA Blog, June 4, 2018, accessed June 26, 2018.
2. FDA, Emerging Technology Program, accessed June 26, 2018.
3. C. Chen, “FDA Repays Industry by Rushing Risky Drugs to Market,” ProPublica.