American Pharmaceutical Review Supplement, April 2015
Sponsor companies developing innovator therapeutics for today’s pharmaceutical markets are feeling intensified pressure to control costs and expedite time to market approval. While safety and efficacy ultimately dictate the success of a new drug, other factors such as the manufacturing strategy and execution can greatly impact the cost and timelines of a drug development program or even derail it.
For small-molecule drugs, many sponsor companies today outsource the development and manufacture of the active pharmaceutical ingredients (APIs) to contract manufacturing organizations (CMOs). This article speaks to the critical importance of identifying the right CMO partner and strategic approach to filing the chemistry, manufacturing, and control (CMC) section of an investigational new drug (IND) application.
New drugs in the United States must receive a marketing authorization from the Food and Drug Administration (FDA) before they can be marketed to healthcare providers and patients on the open market.1 The clinical path to market approval begins with an investigational new drug permitting a compound to begin evaluation in clinical trials.1 An IND application provides the FDA with basic information about the drug substance, formulated drug, and clinical trial design.2 As the drug candidate progresses through further phases of clinical testing, additional CMC data are required.3
As a result of the changing dynamics in the pharmaceutical industry, including the shift of growth to emerging markets that prefer lower-cost drugs and away from blockbusters to therapies designed for smaller, more targeted patient populations, there is significant pressure on drug companies to bring innovative products to market more quickly than ever. To do so means getting potential candidates into clinical trials more rapidly.
The decision to conduct clinical trials is a significant one. Early-phase clinical testing in humans can cost millions of dollars, while later-phase trials can cost a drug company tens to hundreds of millions of dollars. Because the amount of CMC information required for an initial IND is limited and largely related to ensuring the safety of trial participants, many pharmaceutical firms tend to focus their efforts on designing an efficient and effective clinical trial protocol and develop the minimal amount of data required to support the safety of the drug substance and initial formulation.
Such an approach can have significant consequences as the drug candidate moves through further phases of clinical study and hopefully into commercialization. Developing more extensive CMC data from the start often is a far more effective approach to minimizing both risk and overall project timelines.
The forces at work in the pharmaceutical industry are also driving greater use of contract manufacturers throughout the entire drug development cycle, from the discovery stage through the commercial production, and even for patent-life extension activities. When it comes to projects supporting IND applications, it is imperative that sponsor companies select a CMO that has a thorough understanding of the IND application process and recognizes the value in developing appropriate regulatory data. In addition, because communication with FDA is crucial to the successful acceptance of IND applications by the agency, a CMO that has a strong, positive record of compliance and an effective system for communicating with all interested parties, including the sponsor organization, the regulatory bodies, and the clinical trial team, is an ideal partner.
The IND Application
Clinical trials will only be planned for a drug candidate if the results of initial animal studies suggest that it has potential efficacy and the results of initial toxicological evaluations suggest the compound is safe for use in humans. Once the decision to conduct a Phase I clinical trial has been made, data that establish that the product will not expose humans to unreasonable risks during early clinical testing must be developed for inclusion in the IND application.1
There are two categories of IND applications: 1) commercial applications submitted by the pharmaceutical company intending to manufacture or market the drug, and 2) research applications, which are generally submitted by research institutions.4 Three other types of IND applications4 are: 1) Expanded access, sometimes called “compassionate use,” IND applications are for drug candidates that have the potential to be effective for the treatment of unmet medical needs. 2) Emergency IND applications allow for the use of a new drug in a variety of situations where there is insufficient time to pursue a conventional IND application. 3) Investigator-initiated IND applications are submitted by physicians who also perform the clinical study, often to test an existing drug for a new indication or in a new patient population.
It is important to note that IND applications are required not only for new drug substances, but also for existing drugs that are being considered for other uses, including new routes of administration or different dose levels, for treatment of the same disease but in a different set of patients, and for new therapeutic purposes.4 An IND must be filed prior to initiating human trials.
Regardless of the category, type, or reason for an IND application, all submissions must include the results of animal pharmacology and toxicity studies (and any human data if the drug is an existing product) that demonstrate the drug is reasonably safe to use in humans. Information on the chemical structure and properties of the drug substance, the composition and properties of the formulated drug product, the manufacturer, and the manufacturing process and analytical controls used to produce both the drug substance and product (both of which comprise the CMC section) is also required. Of course, detailed protocols for the clinical study and information on the investigator that will be running the trial must also be provided.
The FDA has 30 days to review an IND application to determine whether the drug candidate is safe for use in the proposed clinical trial.1 This decision is in large part based on the results of animal toxicology and efficacy studies as well as the identity, strength, quality, and purity of the drug as presented in the application.
If information is deemed lacking, the FDA may conduct an inspection to further assess the risk, place a hold on the trial, or even terminate the IND application.4
Importance of Developing Appropriate CMC Information
The quantity and type of information required in the CMC section of an IND application varies with the phase of the clinical trial. Less information is required for Phase I trials because patient safety is the main concern and is addressed by the pharmacology and toxicity data. Initially, only a limited number of healthy volunteers are employed in Phase I safety studies to limit risk (with the exception of oncology studies, where oncology patients participate in Phase I trials as the agents under investigation are often quite toxic to a healthy person). Such studies are short-term and conducted under very controlled conditions. Finally, only limited drug substance and formulated product have been manufactured, so there is little data available, and the manufacturing and analytical processes will be improved as the drug progresses through further development.
It is very important to recognize, however, that additional data will be required if the candidate drug does go on to Phase II and Phase III studies. Consequently, in some cases obtaining more extensive data prior to submission of the initial IND application for a Phase I study can be more efficient and productive and help reduce project timelines.
Obtaining more extensive data prior to submission of the initial IND application for a Phase I study can be more efficient and productive and help reduce project timelines.
In addition, while current good manufacturing practice (cGMP) activities that are appropriate for Phase I clinical trials must be followed during the production of the drug substance and drug product, the detailed understanding of a manufacturing process required for commercial use is not expected.5 While a deep understanding of the manufacturing process from the beginning may initially require additional time and effort, the consequent additional control measures do help reduce the risk of failure to produce the API and drug product of appropriate quality required for the clinical study. That additional control is also appreciated by regulatory bodies.
The choice of producing Phase I material according to the minimum requirements versus a more detailed study of the manufacturing process at an early stage is just one example of the decisions that sponsors must make regarding CMC data and information that can impact the overall project with respect to its budget, timeline, and quality, the latter two of which can directly impact the success of the clinical trial and potential patient safety.
The clinical trial cannot proceed without available supply of the candidate drug in a form appropriate for the study design. Therefore, adequate time must be allowed in advance of the start of the clinical trial for development of a CMC package that will include information sufficient to convince regulatory agencies that the drug product is safe for use in the planned study. This information includes evidence for the structure and purity of the API, stability study results indicating that the drug product will be stable during the period of the clinical trial, and descriptions of both process and testing methodologies and quality control systems.1-4
It is important to stress that development of data for both the API and the formulated product is required, and while it is expected that the manufacturing processes ultimately used for commercial production will likely be different from those in the Phase I IND application, sponsors should be careful postponing the development of the formulation intended for later clinical trials without adjusting the overall project schedule, as they may find it difficult to meet the supply requirements for those trials. Process changes should not introduce new impurities as bridging studies will be required to prove that those new impurities are not toxic to patients.
The Role of the CMO
Information on the manufacturer of any pharmaceutical intermediates, the API, and the formulated drug must be provided as part of the CMC section of an IND application. That includes CMOs. The CMO is also typically involved in discussions with FDA about the CMC package and is responsible for at least identifying the need to make any amendments to the initial IND. Amendments are required if changes in the CMC information may have an effect on patient safety, such as the use of a different process route, the appearance of a new impurity after switching to a new synthetic method or a new raw material supplier, or a problem with a container closure resulting in a product quality issue.1-3
The basic requirements for a CMO include extensive expertise and state-of-the art technologies for API synthesis and/or drug product formulation, an effective quality program, a history of regulatory compliance, a strong track record of on-time or accelerated delivery, and available capacity, appropriate lead times, and reasonable project pricing. These qualities are insufficient, however, if the sponsor intends to rely heavily on the CMO for management of an IND project. Extensive experience in carefully balancing the financial, project timeline, and regulatory requirements of an IND project is crucial. The ability of a CMO to make rapid decisions based on all three considerations will have a direct impact on the success of an IND project.
A deep understanding of regulatory requirements is a key attribute that a CMO must have in order to successfully complete IND projects. An understanding of the requirements and assembly of a good CMC package will afford an efficient review of the IND. From the first pre-IND meeting with FDA to discuss the CMC and determine any specific agency requirements related to the particular API or drug product to the End of Phase I (EOPI) (and EOPII) meeting,6 the CMO plays a major role in ensuring that the agency’s CMC requirements are met on a continual basis and that FDA regulators remain satisfied that the drug product is safe for use in the clinical study.
CMOs should also have effective communication and project management strategies in place for interacting with the sponsor company and the group performing the clinical study. In order to make the most appropriate decisions regarding project timing, the extent and type of development work, a CMO must stay apprised of the goals of the sponsor. In addition, while CMOs are not involved in the actual clinical study, they must be aware of the timeline for the trial and the goals of the study to ensure that the appropriate materials are produced when they are needed.
1. Code of Federal Regulations, Title 21, Part 312. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=312. Accessed 2/1/2015.
2. FDA Guidance for Industry. Content and format of Investigational New Drug applications (inds) for phase 1 studies of drugs, including well-characterized, therapeutic, biotechnology-derived products. November 1995. http://www.fda.gov/downloads/Drugs/GuidanceCompliance-RegulatoryInformation/Guidances/UCM074980.pdf. Accessed 2/1/2015.
3. FDA Guidance for Industry. INDs for phase 2 and phase 3 studies–chemistry, manufacturing, and controls information. May 2003. http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070567.pdf. Accessed 2/1/2015.
4. FDA Website. Investigational New Drug (IND) application.
approvalapplications/investigationalnewdrugindapplication/default.htm. Accessed 2/1/2015.
5. FDA Guidance for Industry. CGMP for phase 1 investigational drugs. July 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070273.pdf. Accessed 2/1/2015.
6. IND Meetings for Human Drugs and Biologics – Chemistry, Manufacturing, and controls information. May 2001. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070568.pdf.
Accessed 2/1/2015; FDA Guidance for Industry. Formal meetings between the fda and sponsors or applicants. May 2009. http://www.fda.gov/downloads/