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THE BIOTECH INDUSTRY’S DAILY MONITOR
Supplying global clinical trialS: KeyS to avoiding coStly delayS
Getting clinical trials right, and right the first time, is crucial for biopharma companies, especially as the cost of getting a drug to market is skyrocketing—a piece in Forbes estimates drug development costs have reached the eye-watering level of somewhere between $4 billion and $11 billion (1). R&D returns have therefore fallen drastically and are around half what they were 10 years ago, explains Ian Shott, managing director and principal consultant at Shott Consulting: “Attrition is the overriding driver of cost, with a preclinical success rate of 0.01% and a success rate in the clinic of 10% or less.” The larger part of the cost of clinical-stage drug development comes from clinical trials. According to Timothy Scott, president of the U.S.-based pharmaceutical chemistry development organization, Pharmatek Laboratories, Phase II costs can range from $4,000-$20,000 per patient. So, the last thing a drug developer wants is any kind of interruption of a trial, or to have to start a trial all over again, and this makes the reliable supply of clinical trial material (CTM), whether manufactured in-house or outsourced to a contract manufacturing organization (CMO), absolutely critical. “An interruption in the provision of the clinical trial material … could require that trial to be conducted over again,” Scott says. “And … there is the cost of missed opportunity in the marketplace. If the drug being developed has the potential of being a billion-dollar drug, that is nearly $3 million in lost revenue every day the drug is not on the market.” “Drug developers need sufficient supply; otherwise there will be delays in development,” says Anders Fugelli, head of business development at Lytix Biopharma. “It’s a step-by-step process; first you need a supply for animal testing for safety and toxicity, and then you need to scale up for quantities for clinical trials.” Having a sufficient drug supply for the clinical trial is very important for the patient as well. Problems with manufacturing can affect patients’ welfare; clinical trials can be vital stages in patients’ treatment, especially those with advanced disease or with diseases for which there are few other available treatments. “Once you’ve started the trial, you don’t want it to be shut down or delayed for any reason. … Firstly, you don’t want to interfere with patient care, especially if your investigational drug is showing a clinical benefit, and secondly, if you can’t keep the trial going, you can’t meet your drug-development goals. … The quicker a trial completes, the faster the drug can get to market,” says Gavin Choy, vice president of clinical operations at Astex Pharmaceuticals. These delays can be particularly costly for venture capital–backed companies, says Tom Woiwode, chief operating officer at Okairos, a European clinical-stage biopharmaceutical company. This is because these companies typically have a smaller margin for error than large drugmakers. Clinical trial supply isn’t just an issue for investigational drugs. Some clinical trials compare the study drug against a placebo; however, others, particularly those for serious diseases for which it would be unethical to withdraw active treatment, compare with a marketed drug or another investigational drug. Other trials combine an investigational drug with another drug in a combination therapy. It’s vital for these trials that there is a constant supply of the comparator or combination drug as well as the investigational drug. Maintaining this kind of reliable clinical trials supply needs a robust supply chain. “This requires complex planning to orchestrate the various elements that need to be brought together to have the right supplies ready in the right place at the right time,” says Gerry Hepburn, chief operating officer, vice president and general manager, clinical supply services, Catalent Pharma Solutions. l By Suzanne Elvidge thank you to our SponSor:
When it all goes wrong: Case study: Clavis Pharma
1 April 2 012
To outsource or not to outsource, that is the question
Trimming Timelines with Strategic Partner Selection *Sponsored Content*
Picking the right manufacturing partner
Getting the regulatory issues right
Finding the right time
Looking to the future
April 2 012 2
and we now expect to complete the recruitment in this important study during the second half of 2012 and to have data available in the first quarter of 2013. Global events in recent years. Clavis Pharma also has a drug code-named CP-4126 in pivotal Phase II trials for the treatment of pancreatic cancer (12. and this has allowed the company to lift its recruitment restrictions in most countries. but Ben “There are always going to be Venue stated then that it did supply-chain issues.S.” CP-4126 (also known as CO-101) has not been affected by this delay as it is not manufactured by Ben Venue Laboratories. 13). 6). lean manufacturing processes. such as comparator sourcing. Endocyte’s recurrent. a wide range of cancers and often The lack of access to Doxil used as a comparator drug in clinislowed Eli Lilly’s trial of tasisulam cal trials. One of the approaches that Clavis Pharma used was to manage its stocks of elacytarabine very carefully and control recruitment. Johnson & Johnthe gap (11). Manufacturing and Control [CMC] group with updates on clinical trial usage and enrollment.” Hepburn says. such as other of 2012 (6. It has also found an alternative supplier. The unit was which is used as a comparator drug voluntarily shut down in Novemin clinical trials. in Phase III trials. 9). Johnson & Johnson’s Doxil illustrates the impact of drug shortages. for example.” l Case study: Clavis Pharma—manufaCturing issues Cause CliniCal trial delays Background: Clavis Pharma is developing elacytarabine as a treatment for late-stage acute myeloid leukemia. “The speed of recruitment into CLAVELA has been as planned. and a pivotal Phase III study. platinumAlready in short supply. including Clavis Pharma’s elacytarabine. this can have a huge effect on the supply of clinical trial material. outcomes: Clavis Pharma has dealt with this issue by managing its stocks of elacytarabine very carefully to make sure that patients already being treated are not affected. Clavis Pharma has signed an agreement with Baxter Oncology to transfer manufacturing. viCE prESidEnt of CliniCal ratories in November 2011. turer of the drug. Results are expected toward the end of 2012 (12. started recruitment in June 2010. this shows how important it is to have a second supplier in hand (as Clovis Oncology has) to avoid delays in critical studies. or even communication breakdowns (2). and these unfortunate outcomes can have a number of different causes. a unit of Boehringer Ben Venue Laboratories plant also Ingelheim and the sole manufacmanufactured methotrexate (9). l April 2 012 4 .” says Olav Hellebø. detailed project management. we make sure that we plan contingency activities to avoid a failure in supply. as do monthly meetings with our Chemistry. known as LEAP. and opErationS at aStEx pharmaCEutiCalS Canada has banned a number of drugs from the plant as well (8. site of Ben Venue Doxil with Doxil alone (10. “This includes alternate. or the ability to Medicines Agency (EMA) transfer stocks of drugs issued a number of recalls of between clinical trial centers as oncology and antiviral drugs a last resort. Government Accountability Office.com FierceBiotech THE BIOTECH INDUSTRY’S DAILY MONITOR When it all goes wrong… By Suz anne elvidge Problems in the supply of clinical trial materials from the manufacturers can cause delays and cancellations of trials. such as other suppliers. OH. 13).S. and Baxter released the first batch of elacytarabine in March 2012 for clinical use. and by timing its recruitment for when the next batch of drug becomes available. It also threatened to affect way that relied on Doxil (4).” Scott says. In November 2011. such as the Icelandic volcano ash and severe winter weather. and enabling technology for supply-chain and inventory management. The drug’s licensee. inadequate supplies of the ingredients for the drugs. particularly cancer and nutritional drugs. the resistant ovarian cancer trial. is using two manufacturers for its clinical trials and potential commercial supply and has sufficient supplies in-house of both CP-4126 and gemcitabine. Ben Venue son approved a single in-process Laboratories manufactures investigational drugs. tested our backup logistics routes that allow us to continue to deliver supplies to patients. In addition. there as a treatment of ovarian cancer were around 30 clinical trials under (4). which shortage of Doxil was worsened compared the combination of its by manufacturing problems at the experimental drug EC145 and Bedford. qualified providers and internal backup sites to ensure options are available to complete work. Choy supports this as a mitigation approach: “Having electronic inventory solutions does help. Delays like this can have a significant effect on patients and could make the difference between success and failure for a small biotech company. 7). Food and Drug Administration] audit. streamlined packaging and labeling operations. shortages of drugs. and we are disappointed that the issues at Ben Venue Laboratories are now slowing down this progress.” Choy says. “There are always going to be supply-chain issues. Challenges & obstacles: Clavis Pharma’s Phase III trial for elacytarabine has been delayed because of manufacturing problems at Ben Venue Laboratories. The final batch from Ben Venue Laboratories has also been released. a strike at a Sigma Pharmaceuticals warehouse delayed shipping of drugs in Australia (3). but we always try to have contingency plans in place. and the manufacturing issues have delayed development (see case study). Clovis Oncology.FierceBiotech. “When a CMO shuts down operations due to poor business management or an FDA [U. which is a delay of around three months (12. “We are working closely with Ben Venue Laboratories and Baxter so that we can resume full-speed recruitment as quickly as possible. logistics services. Other causes of plant shutdowns include strikes. The European suppliers. or the ability to transfer stocks of drugs between clinical trial centers as a last resort. but we not expect any further batches always try to have contingency to leave the plant until the end plans in place. Doxil is a liposome-encapsulated form of doxorubicin used to treat 3 April 2 012 batch of Doxil for release in December 2011. the trial’s comparator drug for the pivotal Phase II trial. “At Catalent.” CMOs also play a role in managing supply issues and will have tools in place. The Laboratories. Clavis Pharma CEO.” produced at Ben Venue LaboGavin Choy. This means that results from the trial are now expected in the first quarter of 2013. The first approvals from regulatory agencies to introduce clinical trial material from the new contract manufacturer have been granted. According to the U. key takeaways: While manufacturing issues are often entirely unforeseen. With its partner. known as CLAVELA. and most of these are caused by manufacturing shutdowns. Suppliers Hospira ber 2011 after equipment failures and Mylan have been asked by the thought to result from a lack of FDA to increase production to fill maintenance (5). Clovis Oncology. These were factory-wide and not connected specifically with elacytarabine. 13). Any of these can have an impact on supplies of comparator drugs or drugs used for standard of care. have tripled since 2006.
a CMC director would love to have everything in-house. they primarily worked to be FIPCOs [fully integrated pharmaceutical companies] and kept all work in-house or with large strategic partners. Depending on type of clinical studies.com FierceBiotech THE BIOTECH INDUSTRY’S DAILY MONITOR To outsource or not to outsource. but most now have project teams that work on each new compound.” Shott says. l the risk of unforeseen regulatory issues. client services manager at genetic testing laboratory Correlagen Diagnostics. number of countries served. innovators find the following traits crucial to success. real-time/on-line supply chain data and support Having real-time. The first decision is whether to keep manufacturing inhouse or to outsource it. whereas larger pharma companies tend to keep manufacturing capabilities in-house. secure internet based access to your clinical supplies data and electronically linked sites can assist in many ways from forecasting to spotting supply chain trouble before it happens. which is due to close by the end of 2012.) R&D operation. “Most big pharma companies are restructuring. Specific capacity and expertise in the areas of controlled substances. and Fawdon.FierceBiotech. automations and has industry expertise. how to plan to get it right. This has a knockcontinued on page 7 April 2 012 6 . cytotoxics/potents and cold chain supply will also play an increasing role as the market evolves. shrinking the true global footprint. or whether to try to balance both approaches. and what resources it has available outside the company. there are a few key questions that can help.” says Al Gunduz. greater service and peace of mind throughout their strategic partnership. Not all large pharma companies work this way. Capacity. For large pharma companies. • are there a sufficient number of global sites? Having many geographically separated sites provides advantages of risk minimization against supply interruption. • Clinical manufacturing – the more dose forms supported. Today. a drug developer can expect to experience fewer delays.K. • packaging and labeling – it’s all about the volume and technology. “Ideally. In general. patient recruiting and clinical trial supply chain management. and we’ve seen what happens when it goes wrong—now. When selecting partners. the better. IVRS. Though clinical trial supply is the last step. However. expertise and continuous innovation Strategically. 1. will be shutting up shop by the end of 2015 (14). The decision is actually a default one for many companies.” Scott says. and frequency of depot audits as these items can greatly reduce the risk of trial delay from depot shortcomings. and global quality systems to name a few. Seek suppliers with excellent regulatory compliance histories and hard to get licenses to reduce Sponsored Content 3. many smaller biotech companies contract out their supply chains. because they don’t have the capacity to manufacture in-house.” Trimming Timelines with Strategic Partner Selection Clinical trial planning for fast. and utilizes whichever resources help it achieve its CTM supply goal. For example. around 30% of the big pharmaceutical company pipeline has been cut. that is the question By Suz anne elvidge efficacious. 4. 2. • do the sites have the necessary regulatory approvals/ licenses? The lack of regulatory approvals at a site can effectively render it useless to your needs. and consistent quality and compliance standards across sites. • other Services – Regulatory consulting. “Over the last four years. By selecting a clinical supplier that meets these criteria. automated syringe plunger insertion. label printing. as these suppliers typically work very closely with regulators. seamless multi-country supply. as he or she would have better control of the 5 April 2 012 process. reduced costs. capacity. Sanofi has cut a number of facilities. The companies have capabilities in-house. and specialty handling capabilities make a strong case. a U. volume of shipments. the large pharma industry has evolved its business model to integrate outsourcing. High-speed blinding and labeling. the breadth of their cold chain and controlled drug capabilities. “The biggest advantage to outsourcing for a small pharma company is that they don’t have to build the infrastructure to support development and manufacture of their clinical trial material. But to assess if a clinical supply chain supplier is appropriate for your needs. what resources it has available in-house. it is a critical step in which many innovators don’t have in-house expertise and are seeking strategic partners to compensate. Many suppliers also provide expanded insight that goes beyond finished goods to include complete inventory management. “They can focus all of their cash on answering the question of whether their drug is safe and Many of the big pharma companies are cutting manufacturing and R&D around the world. • how robust is the network of depots? Selecting a supplier with a robust network of depots includes considering their on-time shipping record. OutsOurCing We’ve discussed how important a reliable clinical trial supply is. • Warehousing and distribution – diverse locations. this is limited by company size and resources. The team looks at its plan requirements. purchase order and invoicing information. local and diverse regulatory knowledge. it is critical to work with a company that continually invests in new technologies. and many other technologies may have a positive impact to your timelines. including Genzyme’s Cambridge (U. 2) providing consistency in quality and delivery and 3) simplifying communication and project management. the service capabilities you may need to consider are: • direct Comparator Souring – proof of established relationships and ability to access the most difficult drug products is key. but they also rely on outsourcing vendors for special capabilities and overflow work. Global scale and reach Defining an appropriate level of global scale and reach is difficult. manufacturing plant that makes Plavix and other drugs for the European market. formulation and analytical support. integrated/custom services Choosing a partner that provides multiple services creates efficiencies and reduced timelines by 1) reducing product handoffs.K. robust timelines involves many aspects from clinical development to clinical manufacturing. shipment tracking. cutting their R&D and manufacturing capabilities and cutting their pipelines. 30 years ago.
some companies are actually expanding to bring this in-house.” the best Of bOth wOrlds The in-house versus outsourcing decision isn’t one size fits all—even for companies that have manufacturing capabilities. specifically for biologics. as companies try to use up inventory and do as much as possible internally. particularly in the design. it had access to the larger company’s good manufacturing practices (GMP) facilities in Rome.” Shott says. versely. particularly specialist stages. Know-how in the manufacture and handling of sterile vials or syringes.” Woiwode admits that Okairos was in a unique position. it made sense to bring the manufacturing back in-house.“ Woiwode says. and short-term reduces the need for CMOs. especially as third-party providers have become more capable and cost-effective.com FierceBiotech THE BIOTECH INDUSTRY’S DAILY MONITOR continued from page 5 on effect. process and formulation patents. However. as it gives the company complete control. They are looking for support from the provider. can be vital.-based contract research organization (CRO) providing services including formulation development.” andErS fuGElli. As an example.S. including over scale-up and product. as companies look to outsource as much as possible. drug preformulation. the relationship does require some investment to allow the sponsor company to ‘feel’ that the provider is an extension of their development process. in 2009. improve pipeline efficiency. “Individual investigational drugs … that are judged the most likely to succeed by large inventor companies are more likely to be kept in-house for manufacture and sometimes clinical trials management. which are more complex and where more things can go wrong. packaging and logistics of clinical trials. avoid procuring expensive equipment. “However.FierceBiotech.” It’s not a one-size-fits-all decision but one that needs to be balanced according to the products in the pipeline and the development timelines. director of pharmaceutical development services at Xcelience. cutting the pipeline reduces the demand for products for clinical trials. this will increase the demand on CMOs.“ We used a CMO for an earlier study but ended up with a year- long delay for an unforeseeable problem. in the long term. as Choy explains: “We decided that we didn’t want to build the supply chain in-house but rather focus on our core competencies. Hepburn explains: “Often. However. it makes good sense to partner with CMOs to manage spending. “However. and clinical supplies manufacturing. and to access proprietary expertise. as a spinoff from Merck.” The decision to outsource versus keep work in-house for clinical trial supply is also driven by pressures to reduce costs and get to market faster. but as we were the only company working in chimpanzee adenovirus vectors and we know our technology so well. “Keeping manufacturing inhouse does provide a comfort level for companies in that colleagues and capacity are available close to hand to support the development process. choices still have to be made. “Large pharma companies such as GlaxoSmithKline have the in-house competencies and infrastructure to manufacture drugs for pilot scale and even for clinical trials. as well as to its experience and know-how.” Hepburn says. “We started by outsourcing the manufacture of our adenovirus vectors and vaccines. This was just an unfortunate situation and was not the fault of the CMO. giving it bulk manufacturing capabilities for monoclonal antibodies (15). including refrigerated and coldchain experience.” says Paul Skultety. and this is the ideal.” While the trend has generally been to sell off manufacturing capabilities. a U.” The outsourcing route is the one taken by Astex. This is particularly true of biologics. especially as the needs for clinical trial supplies increase in later stage and global clinical trials. Hepburn supports this: “Outsourcing allows a company to focus on core development. even most big companies will need to outsource because of the quantities needed.” KeePing it in-hOuse The advantage of keeping development in-house is the level of control that the company is able to hold on to. hEad of BuSinESS dEvElopmEnt at lytix Biopharma CMOs may also be brought in to carry out part of the process.” l April 2 012 8 7 April 2 012 . as these capabilities are still finite.” Fugelli says. even most big companies will need to outsource because of the quantities needed. by the time the drug reaches Phase III. “For much of the pharma sector. in-house manufacturing can also be seen as a costly and underutilized resource that has come under pressure in recent years as the cost pressure on development has increased. Biologics and other complex molecules and products are also likely to remain in-house where possible. the high-risk products are more likely to be contracted out by these companies to a CMO. biopharma companies have great expertise in the discovery phase for their products but require assistance to complete the development. The scale of the outsourcing providers is sufficient to drive some economies. “Con- “By the time the drug reaches Phase III. Genentech Singapore (Roche) opted to buy Lonza’s cell-culture biologic manufacturing facility in Singapore.
we can ensure a faster path to clinical and beyond. They almost act as a consultant. and to make sure that its working styles are a good fit. particularly for preclinical trials. SUPPLY CHAIN EXPERTISE We have 25+ years of experience providing global clinical supply chain solutions for more than 4. Europe and Asia. from small to large and from specialist to one-stop shop.” Woiwode says.9% on time delivery record.FierceBiotech. we help you solve your clinical supply challenges with a 99.” Woiwode emphasizes the need to look for the right experience. and this is what a small biotech company needs. and you can often find out about this through word of mouth. UNMATCHED CAPACITY Our capacity includes 100+ clinical packaging suites. The partner must have credibility.catalent. The process starts with defining the criteria: What do you need to know about the CMO? Is size an issue? What technical competence is needed? Are there any requirements for location? Do you want to stay with the same partner throughout? Do you need a backup? to confirm its quality and reputation. and they are found worldwide. GLOBAL NETWORK With 9 facilities in North America.5x11. state-of-the-art automation. Better treatments.com FierceBiotech THE BIOTECH INDUSTRY’S DAILY MONITOR Picking the right manufacturing partner By Suz anne elvidge If a company does decide to outsource its manufacturing for clinical trial supplies. both © 2012 Catalent Pharma Solutions. “Price is important. With of integrated solutions that include formulation development. and manufacturers have to be able to follow this.500 trials of all dose forms and phases.” clinical supply CATALENT HAS ACQUIRED APTUIT’S CTS BUSINESS integrated clinical supply solutions.com Visit: www.000+ shipments a year to over 80 countries. More products. “Different types of company (segments) will have different priorities and needs. Reliably supplied.indd 1 April 2 012 3/9/12 12:10 PM 10 . reduced timelines. particularly for companies working with biologics. but this is a secondary issue. multiple dose form manufacturing. whereas others will offer advice and support. that if they can support small companies. the next step of the process (and maybe the hardest one) is to find the right partner. RELIABLE PARTNER With our strong project management and operational excellence. We have a solution. to market the world’s #1 partner for drug development and formulation services. for customers of all sizes. and even help with documentation. will have a pipeline of drugs but not the resources of a big pharma company. it’s important to know what a company has done before and how it works.™ DEVELOPMENT DELIVERY SUPPLY Every clinical trial has a challenge. Some CMOs will just do exactly what they are told and focus on the manufacture. I think this would be an important thing for a CMO to learn.” Fugelli says.” Shott says. The large companies have very structured selection and approval procedures involving multifunctional teams and characterizing the suppliers on a scale from tactical through to strategic or preferred. “What I wish we had known before selecting a CMO was how it actually worked on a day-to-day basis. These companies will tend to make decisions based on value rather than just the lowest cost. Catalent is now a broad range supply. and from recommendations through your networks. All rights reserved. such as personalized cancer vaccines.com 8918 CSS Alternate Ad 8. Call: + 1 888 SOLUTION (765-8846) Email: solutions@catalent. whereas midsize companies 9 April 2 012 size isn’t (always) everything Sometimes using a small and lowcost CMO is the right approach for the early stage of development. “Companies are developing ever more complex therapeutic modalities. Catalent. “Small biotechnology startups are more driven by person-to-person relationships and have to depend on outsourcing functions and capabilities downstream of discovery. analytical trial. “You need to find a CMO that has experience in the same or a related system. make creative suggestions. a new world leader in clinical trial supply. as the huge costs of clinical development continued on page 11 it’s bOth what yOu KnOw and whO yOu KnOw Before making a decision. clinical trial testing and commercial manufacturing. they will stick with them through to Phase III. and 50+ depots around the world. Which one to choose depends on the stage of development of the drug and the company’s needs and available resources. and industry-leading cold chain and GMP warehousing.” There are all kinds of CMOs. so you are looking for experience as close to yours as possible. we provide 150.
“To gain approval for a cell-based biologic. the ability to remain flexible and responsive to changes in product-development strategy is crucial to program success. poor solubility.” Choy says. companies may opt to work with a local company or a company that has certain specialization. especially as pharma markets are growing in Asia and Latin America.” Scott says. give or take. “More often than not these days. and often are under way farther afield as well. The decisions may be cost-driven. and then rank the available CMOs according to their capabilities and other criteria—for example. A good approach is to create a spreadsheet listing the requirements.” lOOKing at the KnOw-hOw The right CMO has to have the right competencies to be the perfect fit. “We find that for this segment.FierceBiotech.” staying all the way The decision whether to use different CMOs for early and late stages of clinical development will differ from company to company and project to project. it’s important to look at scalability and capability upfront. and Europe. companies many times will look for economies of scale anywhere in the world. the company will be spending tens of millions of dollars on CTM and commercial supply. However. even basic requirements such as the production of water for injection can vary between FDA-regulated and EMAregulated facilities. and minimize handoffs by coupling manufacturing. A CMC director will have to visit those API production and CMO locations frequently. as well as the ability to ensure integrity of clinical trial material under a wide variety of transportation and storage scenarios.U. Access to expertise. In the later stages. If a drug developer is going to change CMOs after Phase I or Phase II. “CMOs will charge for development of process (engineering runs) and development of auxiliary testing. help them overcome stage-specific constraints such as amount of API. In Phase III and commercial stages of CMC development. lOCatiOn. and it is important to be aware of this when changing continued on page 13 April 2 012 12 .” Fugelli says. and responsiveness are key to early-stage success. In the early stages. if you have a good relationship with them. wherever they are located. cost. or one based in a developing market. bioavailability or PK issues. “Scale is an important consideration. scalable equipment. “Typically. “Because I believe. maximum or minimum batch sizes. Hepburn explains: “Particularly in trials that use comparators which can be region. need to be compliant with the needs of the EMA. Clinical trials to be performed in the E. there are situations in which a local CMO is more important. the formulation is mostly established and it is really a matter of scale-up.or market-specific.” Skultety says. so he or she may want them to be as local as possible. it becomes easier to transfer its development across to an outsourced manufacturer. they need to work with a company that can make the handover as smooth and seamless as possible.” Hepburn says.” timothy SCott.” Woiwode says. prESidEnt of pharmatEk laBoratoriES outsource their early phase work to accelerate candidate choice or elimination. for these. it’s important to bear in mind that changing CMOs partway through the process can have certain cost implications.S. or particularly good service for this early phase work. Altering the formulation of biologics can have serious clinical consequences. lOCatiOn By Phase III.” Skultety says. However. 11 April 2 012 “The need to align clinical supply with study demands that span a global network of clinical sites has driven changes in supply-chain strategy. ability to carry out formulation development or filling and packaging.” Skultety says. We work with clients to understand their overall productdevelopment goals and timelines. where possible. packaging and distribution all at one site. This continues to be a significant driver of the CMO choice.” In this era of global communication and global clinical trials. and so the drug developer needs to be prepared from the beginning to change source. Woiwode recommends manufacturing using the same CMO for all trials globally: “Stick with who you know. too). and changing CMOs will mean duplication of these services. the location of the clinical trials and the location of the CMOs are not dependent upon one another within the United States.” Gunduz says. should be compliant for both the U. “At those stages.” The requirements are different in the United States and Europe.” However. a CMC director will choose a CMO in the E. “Some companies want to maintain control and keep very early phase work internal and outsource the work at Phase IIb and beyond. At that point. can be cheaper. but this is not a statutory requirement. The better CMOs within the U. as a small CMO.” Scott says.U. Virtual companies obviously need to outsource the complete process. and it’s important to be aware of these (and be satisfied that the CMO of choice is aware of them. with lower overall cost and many decisions. and this part of the CMC can make or break the program. “The right documentation and permissions. most clinical trials are at the very least being conducted in the United States and Europe.” The decisions will also vary based on the company’s internal resources.” “At the early stages of manufacturing.com FierceBiotech THE BIOTECH INDUSTRY’S DAILY MONITOR continued from page 9 mean the tenet is wherever possible to fail fast and cheap. but not as important as finding a partner who meets your stagespecific needs. see “Staying all the way. that companies should use the same CMO throughout the development of the drug. lOCatiOn. the costs of CMC are around $2 million for a small molecule. it’s important to have absolute control. because any changes in manufacturing processes need to be made as early as possible in the drug-development process and be flagged up to the regulatory authorities and documented in the submission for approval (16). are critical. as it will be aligned for EMA regulations—for example. you have to use the same cell line for the marketed drug as used in Phase III. “Large pharma companies may do the opposite to utilize internal capacity at a later stage and “Most reputable vendors have experience with regulations for different areas of the world and have the logistics in place to ship to those locations.S. “Typically. the location of a CMO isn’t necessarily the deal-breaker that it once was. One situation where it can be important to have a CMO locked in place is for later stage development of biologics. the need to manufacture and package locally can be critical. a small CMO is unlikely to be able to follow through into later-stage clinical trials. “Most reputable vendors have experience with regulations for different areas of the world and have the logistics in place to ship to those locations.” However. “In Phase I and II. with a lot more budget in play. we see emerging pharma focused on selecting a CMO partner that can get them to Phase IIa or IIb. and their resources for clinical distribution. but as you get to know more about your drug and its manufacturing. as opposed to selecting a CMO provider that can take them all the way to commercial. the number of decisions being made relative to the chemistry and formulation are many and hypercritical.. sticking with the same CMO throughout can also have its advantages. but it’s essential that it has been inspected and approved by the appropriate agencies for all countries where the clinical trials will be carried out.” Gunduz says.
and if a facility isn’t ready for inspection. but the regulators are getting more cautious. For example. If regulatory bodies don’t believe a company is complying. For companies taking this and cold-chain supply manageapproach.” Shott says. but “Pharmaceutical companies are looking for the most effective and efficient lowcost and fastest way to develop a drug. it’s vital that companies (or their CMOs) comply with current GMPs and ensure that the documentation is in place. willingness to “Given the high cost and potential customize and the value of the work and outcomes.” l with as many as possible to keep “Processes and specifications need to be rigorously and comprehensively defined.” tors for early stage GErry hEpBurn. the decisupplier and a backup. viCE providers. and it’s important to have security of supply from a properly inspected and approved supplier. While this might not change the activity or safety of the resulting therapeutic. asking for bigger trials. and the variability of the drugs. and CMOs will need more than one supplier must have the ability to respond because of the scale and to reduce rapidly in order to ensure on-time the risk of issues with any one supdelivery and receipt of clinical plier.” Hepburn says. before Phase IIb. This caution over requirements for clinical trials may stem from the case of Vioxx (rofecoxib). l April 2 012 14 . which was used to treat arthritis. Getting the regulatory issues right By Suz anne elvidge To get a drug approved for market. the manufacturing and supply of products for clinical trials. most trials project requirements. This dual sion to adopt a one-stop-shop sourcing strategy saves problems model versus a portfolio approach like those experienced by Clavis to contract development and manuPharma (see case study). asking for bigger trials.” ian Shott. As an example of this. “Given the high cost and potential value of the work and outcomes. and the drug remained on sale until late 2004. regulatory rigor has varied depending on the stage of development. An example of this is Genzyme’s Myozyme (aglucosidase alfa). “A limited number of companies are more baCKuPs aren’t just tactical in their selection of provider fOr COmPuters and move around between CMOs. CliniCal stage work is driven Supply SErviCES.” Skultety adds. e. which is approved for the treatment of the genetic disorder Pompe disease. “Responsiveness. it’s a good idea to mainment to protect the integrity and tain good connections with all the timeliness of global clinical trials partners. and CMO partners—from high-cost countries. Shott ConSultinG Merck did not react immediately. which can have unexpected effects. but it’s facturing services is a subject of vitally important that both suppliers ongoing debate. This incident led regulators and the public to question the rigor and appropriateness of clinical trial design and execution in chronic drugs. as stage-appropriate manufacturwell as spot suppliers for emergening capacity and scale. prinCipal ConSultant. it can affect its regulatory approval (17). adding more cost and time. Keeping to the same CMO does maintain consistency between phases. but the trend is now toward increasing rigor. approval of Cialis (tadalafil) and a number of other drugs was delayed because of manufacturing concerns at Eli Lilly’s plants in Indianapolis (16). or its level forecast modeling and simulation of risk. Later prESidEnt and GEnEral manaGEr. the GMP requirements have traditionally been less arduous than after. In addition to offering top-tier partners to lower tier. because the differences in the glycosylation meant that the FDA regarded it as a different molecule (18). effective cies—allows drug developers to late-stage CMOs employ technolchoose partners according to the ogy-driven solutions for clinical importance of a project. a change in the formulation of Eprex (recombinant erythropoietin) in 1998 led to the formation of neutralizing antibodies against both the native and recombinant erythropoietin.com FierceBiotech THE BIOTECH INDUSTRY’S DAILY MONITOR continued from page 12 CMOs. “Early phase work can be sus“By the time a drug reaches ceptible to significant fluctuation in global Phase III trials. When Genzyme moved its production to a larger bioreactor at another site. this can delay approval.g. many companies tend to identify a narrow group of CMO partners they trust and have built a relationship with. including variations in process conditions during drug substance and drug product manufacture or indeed variations in minor impurities. The drug was linked with an estimated 27. between trials.” Shott says. particularly where Phase III trials for chronic diseases are concerned. ChiEf opEratinG offiCEr. which need more clinical material.785 heart attacks and sudden cardiac deaths in the 5 years it was on the market between its launch in 1999 and September 2004. and by extension. a form of anemia (17).” Fugelli says. Because of this it’s important to have flawless process control and complete consistency. adding more cost and time. causing a number of cases of pure red cell aplasia. which need more clinical material. but the regulators are getting more cautious. materials. the FDA asked the company to file for approval a second time. Changing the cell line or the manufacturing site can cause variations in glycosylation patterns on the protein surface or changes in the protein folding. 13 April 2 012 the relationships strong and active. when it was pulled (19). and even simply between batches of drugs. which could be due to a range of parameters. “Pharmaceutical companies are looking for the most effective and efficient low-cost and fastest way to develop a drug. In some cases.. manaGinG dirECtor. keeping projects going supply. Variations in clinical trial outcomes are to be expected due to biological variability in the humans taking part in the trials.” It’s important to select a lead According to Skultety. are properly validated. many ability to react within companies tend to identify a narrow short lead times are group of CMO partners they trust and critical success fachave built a relationship with. by increasing clinical trial complexity and an expanding global network Maintaining a portfolio of potential of depots. Problems were first detected in 2000.FierceBiotech. they can refuse to grant approval. investigators. CatalEnt pharma SolutionS.
Looking to the future By Suz anne elvidge The trend across the biotech and pharmaceutical industries is generally toward outsourcing. personnel training requirements. facility requirements. and this helped us in our final selection of the candidate. health & safety audit. health & safety audit. Traditionally. we will see significant outsourcing of manufacturing and support functions. there will be a bigger push for both CROs and CMOs to provide services to fill these needs at a more cost-effective price than doing the work in-house. manufacturing service agreement. companies all over the globe will be able to provide the level of GMP services required and all at about the same price. “In the future. but the drug showed long-term stability issues when the active ingredient came out of solution. providing a valueadded service for those companies that want or need it will become increasingly important (see “It’s both what you know and who you know”).” l April 2 012 16 15 April 2 012 . between teams within companies. “Some items that pharma companies must have in place prior to partnering: quality audit.FierceBiotech. environment. equipment requirements. “Companies that are going to outsource need to start finding a CMO as soon as they have selected their lead candidate. but we asked the CMO to scale up all three to 10 grams. “As the costs of drug development increase. and this is a big responsibility for those who have to manage the process and relationship in-house. l As CMO capabilities grow worldwide and competition becomes more heated. it will be about the quality of the service provided. to support them in making the right decision. I believe the role of CROs and CMOs will become more important in the development of upcoming drugs and generics. However. and the manufacture of supplies for clinical trials seems to be no exception.” Scott says. Shott agrees: “The trend for the future will be towards increased outsourcing. including manufacturing. especially given the increases in costs in China and India. This is the point where decisions may have to be made about changing CMOs. or even … a couple of years before the product goes into clinical trials. equipment requirements. but more importantly.” While this reduces the pressure on companies overall. “Companies are outsourcing more and more throughout drug development. because they don’t pay enough attention. particularly for small pharma or biotech companies signing agreements with large pharmaceutical companies. as if the manufacturing is not put in place in time. “The norm for biotechs is to partner with a large pharma company for the market. personnel training requirements. and losing sight of the formulation and manufacturing issues. quality agreement. This can be the downfall of companies and trials.” Woiwode says. even as far as early-stage R&D. or about bringing manufacturing in-house. Finding a CMO this early means looking at the idea of manufacturing when companies are at preformulation and API characterization stages. it can cause delays to clinical trials that are as limiting as those caused by manufacturing problems.com FierceBiotech THE BIOTECH INDUSTRY’S DAILY MONITOR Finding the right time By Suz anne elvidge Speaking with a CMO at the right time is just as important as picking the right CMO. we selected what we thought would be our clini- cal candidate from three potential molecules. manufacturing service agreement. “For one of our products. it is still very important that people within the drug-innovator company work directly with the CMOs and keep a close eye on the process. Shott says: “Companies need to look at the options for manufacturing right at the beginning and need to improve collaboration between different departments and specialist groups. focusing on the clinical questions. it’s easy to get caught up in moving drug development forward.” Scott says. as the attrition rate of drugs in R&D is around 95%. quality agreement. and Choy has seen the impact of this.” These kinds of practical tests could also help in choosing a CMO. This approach is understandable. facility requirements. prESidEnt of pharmatEk laBoratoriES “Some items that pharma companies must have in place prior to partnering: quality audit. environment. “It will come down to having the required capabilities. but it is important to have something locked in place by Phase II efficacy and dose trials. By 2020.” timothy SCott. Partnering or licensing can change any decisions made about manufacturing.” Fugelli says. with the research teams getting the cheapest source for drug candidates prior to clinical trials. Is the vendor responsive? Do they communicate well with the client and in a timely manner? Does the client feel that the vendor is truly client-centric?” The key to improved reliability of clinical drug supply is better collaboration. The company had to retract the NDA and its stock fell by 40%. He reports a biotech company that had completed its clinical package and submitted its NDA. work has been done in silos. and then development teams needing a more reliable source for later stage trials involving much larger patient populations in the clinic.” Gunduz says. Drug developers need to be fully prepared for discussions with CMOs.” Fugelli says.
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