March 2009 Vol 9 No 3                                                                                    www.drugdeliveryt...
Therapeutic                    Focus                   Cardiology & Oncology Drug Development                   & Regulati...
difficulties proving efficacy or            organizationunexpected safety concerns, particularly    (CRO) can assist aduri...
specified in their biologic license          NDAs (ANDAs) from the US and                 approved drug product, and such ...
Code of Federal Regulations (CFR) 21          such as near-infrared (NIR) or Raman          clinical endpoint such as surv...
market size is currently estimated at about $15 billion in revenue per year and is                   growing at a healthy ...
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Cardiology & Oncology Drug Development & Regulation


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Discusses CMC issues regarding Drug-eluting coronary stents (DES) & Oncology drugs.

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Cardiology & Oncology Drug Development & Regulation

  1. 1. March 2009 Vol 9 No 3 IN THIS ISSUE INTERVIEW WITH DEPOMED’S PRESIDENT & CEO CARL A. PELZEL Combination Devices 18 Abhijit Gokhale, PhD Excipient Sourcing 22 Alen Guy, PhD Solid Dose Injection 24 Charles Potter, PhD Nanomedicine Market 32 Bill Martineau, MBA FEATURING Analytical The science & business of drug development in specialty pharma, biotechnology, and drug delivery Testing Labs 62 Xiaochun Yu, Ms. Cindy H. Mr. Mike PhD Dubin Mesa Cardiology & From Battlefield to A New Approach to Proteins & Peptides: Backpack: Evolution Oncology 68 Threshold Evaluation & Dependent On Advances in Drug of the Auto-Injector Stuart L. Cantor, PhD Quantitation of Unknown Extractables Delivery? & Leachables Using HPLC/CAD
  2. 2. Therapeutic Focus Cardiology & Oncology Drug Development & Regulation By: Stuart L. Cantor, PhD, Senior Scientist, and Kadriye Ciftci, PhD, Senior Director Drug Delivery, ICON Development Solutions reach $80 billion by 2012, according to the development of highly potent, Introduction IMS Health. hydrophobic compounds, and difficulty Heart disease and cancer are still the There are several reasons for this in ensuring their solubility as well as two leading causes of mortality in the increased sales growth, which include specificity to target the tumor site. world. Recent data show that in the US, extended lifespan, increases in obesity Because oncology drugs are cytotoxic, the total direct and indirect costs and hypertension in the US population, maintaining containment facilities during associated with treating cardiovascular an increasing number of patients on the developmental phase for these actives diseases and stroke are estimated to be chemotherapy in major markets, longer can become expensive. Furthermore, $449 billion, by comparison, the treatment periods for a growing number with both of these drug classes, estimated costs for all types of cancer of patients, and the was $219 billion.1 Sales of drugs treating greater availability cardiovascular disorders, hypertension, of more expensive and cancer accounted for roughly 31% of and modern the $287 billion prescription targeted therapies pharmaceutical market in 2007; theseVol 9 No 3 to treat these drugs continue to be the largest therapy diseases. However, classes in the US (Figure 1).2 In the hotly debated cardiology sector, Pfizer’s Lipitor® issues have risen amassed sales revenues of $12.7 billionMARCH 2009 over the long-term in 2007, making it the best selling drug safety of coronary in pharmaceutical history. Not to be drug-eluting stents outdone, the biotech industry has (DES), efficacy of likewise developed a number of beta-blockers in successful blockbuster cancer therapiesSPECIALTY PHARMA treating as intravenous solutions or vaccines, hypertension, and including Herceptin® and Avastin®, the long-term monoclonal antibody-based therapies to safety of statins. In treat breast and colon cancer, the oncology respectively, and Gardasil®, a vaccine sector, there has Figure 1. against cervical cancer.3 Sales of cancer been an increase in drugs are projected to double and could68
  3. 3. difficulties proving efficacy or organizationunexpected safety concerns, particularly (CRO) can assist aduring later-stage development amid company withPhase III trials, can be particularly developing achallenging. game plan for the The increased number of extent of bothblockbuster drugs that are scheduled to preclinical animallose patent protection in the coming testing and futureyears (Figure 2), coupled with the FDA’s clinical trials;Amendments Act of 2007 granting such services cansweeping new powers to the agency for be outsourced bysuch tasks as requiring drug makers to start-up or virtualdo post-marketing clinical trials, are companies withmaking the regulatory climate more limited in-houseexpensive and time-consuming for the drug developmentpharmaceutical industry. Furthermore, resources. Thebecause drug safety issues are CRO can alsoparamount due to highly publicized help the companycases like Vioxx®, the FDA is closely in itsscrutinizing safety data while improving correspondenceits management of safety signals. with the FDA and Table 2. offer guidance physicochemical stability and potentialDrug Development during the critical pre-IND meeting. Under current regulations, a sponsor is immunologic issues need to be closely Oncology drugs in development are monitored and controlled to ensure a permitted to start their clinical trials 30generally highly potent as well as drug product’s beneficial effects. days after filing its IND with the FDAcytotoxic; some may even have narrow “In contrast to most drugs that are unless notified earlier that there aretherapeutic windows. It is important to chemically synthesized and with a issues with the application.assess the safety of these compounds known structure, most biologics are Recent reports from theearly on to determine that they are complex mixtures that are not easily Pharmaceutical Research andeffective in treating the disease process identified or characterized. Biological Manufacturers of America (PhRMA)while not damaging healthy tissue. products, including those manufactured noted that 750 new medicines are beingAccording to the M3 Guidance for by biotechnology, tend to be heat tested in the fight against cancer, andIndustry, single-dose acute toxicity Vol 9 No 3 256 new medicines are in development sensitive and susceptible to microbialstudies are required to be performed for contamination,” says Paul Richards, to treat cardiovascular diseases.5,6 Whilepharmaceuticals and should be FDA Spokesperson at CBER. there have been a number of successfulevaluated in two small mammalian “Therefore, it is necessary to use aseptic anti-neoplastic small moleculesmodel species before the first human principles from initial manufacturing MARCH 2009 launched over the years, such as 5-exposure.4 steps in order to ensure sterility of the fluorouracil, paclitaxel, and The ratio of time for animal to finished products, which is also in doxorubicin, the focus has shifted awayhuman testing is 1:1, meaning that the contrast to most conventional drugs.” from broad-acting cytotoxic drugsFDA will allow a company to conduct Furthermore, vaccine clinical toward the development of new SPECIALTY PHARMAhuman clinical trials for only the same development follows the same general therapies directed against specifictime period in which animal data has pathway as for drugs and other molecular targets. Although biologicsbeen supplied. Sometimes, the agency biologics. However, due to the complex and vaccines derived from larger proteincan also request that safety and/or nature of many vaccines, each lot must molecules offer promise in thesetoxicity data in a non-human primate be thoroughly tested for safety, sterility, therapeutic areas due to their highalso be supplied before an and potency by the manufacturer. These disease specificity and activity atInvestigational New Drug (IND) can be tests, as well as many others that relatively low concentrations asapproved. A contract research manufacturers must perform, are 69 compared with small molecules,
  4. 4. specified in their biologic license NDAs (ANDAs) from the US and approved drug product, and such filings applications (BLAs). If the product is required for European and Japanese can be used to support new and subject to official release by the FDA’s submissions. Canadian INDs must also innovative drug delivery forms. Data Center for Biologics Evaluation and be in CTD format; however, these are from published studies can even be Research (CBER), the manufacturer referred to as CTAs or Clinical Trial submitted to the FDA. However, the must submit samples of each production Applications for Phases I-III. The CTD company would need to provide lot to the Agency together with a release contains several modules with Modules 2 additional clinical data necessary to protocol showing a summary of the lot and 3 containing critical Chemistry, demonstrate any safety and efficacy manufacturing history and the results of Manufacturing, and Control (CMC) differences between the original drug all the manufacturer’s tests performed on information. and the 505(b)(2) drug. Some of the that lot, says Mr. Richards. While Module 2 deals with both different types of applications covered by “The most challenging aspects to non-clinical and clinical overviews and the section 505(b)(2) are: developing these biologic drugs is the summaries, the quality section or design of efficient and robust Module 3 deals only with CMC issues • change in an active ingredient (ie, fermentation and purification processes and provides information on the different salt, ester, complex, and the production of a stable physicochemical properties and control chelate, clathrate, racemate, or formulation,” says Peter Ihnat, PhD, Sr. of the drug substance as well as the enantiomer) for a listed drug Principal Scientist, Protein Therapeutics, development, manufacture, and control containing the same active Bristol-Myers Squibb. of the finished drug product. Modules 4 moiety; Protein formulations can be and 5 address non-clinical and clinical developed using either lyophilized study reports, respectively. Updates to • change in dosage form, strength, powders or liquid parenterals; however, the IND data following Phase I-II trials formulation, dosing regimen, or freeze-drying is not as popular an option can be provided in information route of administration; and/or nowadays due to the increased cost and amendments and annual reports; • change from a prescription longer development time required to however, the emphasis should be on indication to an over-the-counter produce a successful formulation. reporting significant changes that can indication. “Typically, the target level for have a safety-related impact. CMC protein impurities for liquid formulations development will continue in parallel is < 5%, and these are usually due to with the clinical development during The important benefits of using the oligomers or aggregates; however, due to Phase III studies.9,10 505(b)(2) filing route are a faster the immunogenic potential of these If the CMC section will be written pathway toward regulatory approval compounds, impurity levels are for an already approved drug but a new without giving the sponsor the burden of evaluated on a case-by-case basis. dosage form, the Drug Master File supplying duplicate safety and efficacy Moreover, long-term protein stability is (DMF) number, if available, can be data on an already existing compound.Vol 9 No 3 monitored using at least two to three referenced for some of the pertinent However, the FDA does still require that orthogonal methods in addition to an in manufacturing information for the drug a sponsor provide additional clinical vitro bioassay to assess biological substance. For all scientific data, the data, termed bridging studies, which are activity,” says Mr. Ihnat. FDA is particularly concerned that the necessary to support any changes orMARCH 2009 experimental study design and statistical modifications from the listed drug(s) to analysis be sound and free from flaws, the 505(b)(2) drug(s), and these studies Regulatory and requires a rationale and justification will allow extrapolation of the efficacy Submissions used for final specifications selected as and safety data. Furthermore, aSPECIALTY PHARMA The CTD or Common Technical well as the use of novel excipients and 505(b)(2) applicant may qualify for 3 or Document was developed to be used for any unusual tests performed. 5 years of Hatch-Waxman marketing regulatory submissions and finalized as Two other regulatory submission exclusivity.11 the M4 Guidance for Industry in 2004.7,8 pathways available are the 505(b)(2) and The other non-traditional route for This table of contents format is highly combination product options. The regulatory approval deals with recommended for INDs, New Drug 505(b)(2) route offers companies the combination products, such as coronary Applications (NDAs), and Abbreviated advantage of not having to supply the DES, which are considered a drug-70 safety and efficacy data on an already device combination product under the
  5. 5. Code of Federal Regulations (CFR) 21 such as near-infrared (NIR) or Raman clinical endpoint such as survival orCFR 3.2(e)(1). The Office of spectroscopy, to provide real-time process morbidity, and which is reasonably likelyCombination Products (OCP) at the FDA data. PAT finds wide applicability in the to predict clinical benefit. Examples ofassigns such products to a lead agency pharmaceutical industry and can be used tumor assessment endpoints are responsecenter, based upon the product’s primary to assess blend and content uniformity, rate to drug therapy or time to tumormode of action. OCP ensures timely, prediction of dissolution time, and can progression, measured using anatomicconsistent pre-market review and determine the end-point of a coating or imaging techniques. Once acceleratedappropriate post-market regulation of drying operation. Not only can end- approval has been granted, continuedcombination products by facilitating the product testing be reduced, which can marketing of the product will bereview process involving more than one save a company money, but the FDA can contingent on the sponsor’s providingagency center. In this case, the also provide some regulatory flexibility timely and conclusive evidence frominvestigational device exemption (IDE) for any process changes that could occur validation trials that establishes that theapplication would be sent to the FDA’s in the future, provided that they are experimental drug is safe and providesCenter for Devices and Radiological accompanied by scientific justification.13 tangible clinical benefit. The productHealth (CDRH) with significant “The Agency considers PAT to be a approval can be withdrawn ifconsultation by the Office of New Drug tool for designing, analyzing, and confirmatory studies fail to show clinicalQuality Assessment (ONDQA)/Division controlling manufacturing through timely benefits, or if the drug sponsor fails toof Cardiovascular and Renal Products. measurements (ie, during processing) of conduct the confirmatory studies. Many scientific and regulatory issues critical quality and performance attributes A fast-track status is granted by thewill arise due to the complex nature of a of raw and in-process materials and Agency for those drugs also developed tocoronary DES. Some important concerns processes, with the goal of ensuring final treat life-threatening diseases and thatthat would need to be evaluated and product quality. The goal of PAT is to demonstrate the potential to address andiscussed in a submission include acute enhance understanding and control of the unmet medical need. In this instance, aand chronic stent biocompatibility, manufacturing process and to facilitate rolling NDA can be approved that allowspolymeric coating characterization (ie, innovation in development, for completed sections of the NDA to bethickness, uniformity, integrity, adhesion manufacturing, and quality assurance by submitted to the FDA on an ongoingto stent), and drug release profile. The focusing on process understanding. These basis. The FDA strongly recommendspredominant percentage composition of a concepts are applicable to all several meetings, including a pre-INDcombination product does not dictate the manufacturing situations,” says Jon E. consultation, meetings following PhasesAgency center(s) where it is regulated, Clark, MS, Associate Director for the I-II, and a pre-NDA meeting to expediterather, it is the primary mode of action or Office of Pharmaceutical Science (OPS) the approval process. The otherthe “most important therapeutic action of Policy Development at the FDA CDER. designation, priority review, is for drugsa combination product” that determines Due to the serious nature of the showing a significant therapeutic benefitwhere a combination product will be diseases they treat, both cardiology and compared to the standard of care. In this Vol 9 No 3regulated. For example, DES submissions oncology drugs qualify under the fast- case, the FDA would review a NDAare assigned to CDRH because the track drug development program within 6 months as opposed to thedevice’s role in physically maintaining classification. The three designations standard review completion timeline ofvessel lumen patency provides the most given by the FDA are accelerated 10 months. MARCH 2009important therapeutic action of the approval, fast-track, and prioritycombination product. The drug plays only review.14,15 In 1992, accelerated approvala secondary role in reducing restenosis or for oncology drugs was codified into law Outsourcing Keyre-narrowing of the coronary arteries, a under Subpart H (21 CFR part 314.530) Capabilities SPECIALTY PHARMAphenomenon which is caused by the and added to the new drug application In addition to hearing the term CRObody’s formation of scar tissue in regulations. Accelerated approvals are as a common buzzword these days, theresponse to stent implantation.12 granted for the treatment of serious or fact is that both small and large While the agency currently does not life-threatening conditions and a benefit pharmaceutical companies can benefitrequire the use of Process Analytical over available therapy exists. from utilizing the added services andTechnologies (PAT) for their submissions, This designation requires using a expertise of a global CRO while focusingthe use of PAT for CMC documentation surrogate endpoint for efficacy, ie, an on their core competencies. The CROis looked upon favorably. PAT uses tools, evaluation intended to substitute for a 71
  6. 6. market size is currently estimated at about $15 billion in revenue per year and is growing at a healthy annual rate of 14.8%. By 2010, the market is forecast to be in Stuart Cantor, the vicinity of $22.9 billion, according to Frost & Sullivan. A CRO should be chosen PhD carefully at the outset of a project after considering the budget, timelines, the range Senior Scientist of services provided, and the resources offered. A CRO can assist with the review and ICON Development Solutions editing of the regulatory submissions and can either represent the company as their sole agent or accompany their client in meetings with the FDA. For smaller companies with limited resources, limited regulatory expertise, and tight timelines, meetings with the FDA early in the development process can alert the company if they are going down the wrong pathway. Meetings with the FDA can be arranged at both the pre-IND stage, where the Dr. Stuart Cantor graduated from the University of company can ask questions to see if they have done enough work to prove a drug’s Maryland Pharmacy School and is a Senior Scientist safety, and also before going through the time and expense for Phase III clinical trials for ICON. Dr. Cantor currently assists global clients (an after Phase II meeting). These meetings are invaluable in identifying additional with their CMC sections of regulatory documents for safety, toxicity, or efficacy issues pertinent to cardiology and oncology IND/NDA solid dosage forms and biologics, and also handles filings. More frequent interaction with the FDA would be recommended (ie, end of clinical supply chain management issues. He has 7 Phase I meeting) if the drug would be marketed to a small patient population with a pharmaceutical publications online/in-process, and rare disease or condition, ie, orphan drug classification for a disease affecting less has published a book chapter on wet granulation. He interned at Wyeth and Bristol Myers Squibb than 200,000 people in the US. Orphan drugs would also be granted accelerated (BMS) and studied different granulation processes approval status, and NDAs are given a priority review timeline of 6 months. and their mechanical properties. His research A CRO can act as a regulatory resource for a company to guide them as to what covered preformulation, formulation, analytical the minimum agency requirements are to prove safety and efficacy and which tests method validation, blend segregation, and chemical would be superfluous. Another key advantage of using a CRO is that they have the imaging. His expertise is in extrusion- capability to offer their clients a strategic viewpoint on risk assessment and spheronization, wet granulation, and NIR management, and can additionally shoulder some of that risk in interactions with the spectroscopy. Dr. Cantor previously developed the FDA. The Agency will take a global view of the scientific data to assess the risk- sugarless fiber chews for diabetics launched by benefit ratio, ie, the benefits of the drug substance and final drug product must far BMS under the Choice® DM brand. outweigh any complications or potential risks to human health. The Agency also examines what therapeutic advantages the new product has over therapies currently in Kadriye Ciftci, the market. Sometimes there is no information available on comparator products as PhD the regulatory submission is for a first-in-class therapy. In such instances, a CRO can Senior Director Drug provide key information as it can draw from a wide knowledge base from past client Delivery experiences with a variety of dosage forms. N ICON Development SolutionsVol 9 No 3 References 1. Rosamond W, et al. Heart Disease and Stroke Statistics 2008 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. [Available at: (DOI: 10.1161/circulationaha.107.187998); Accessed August 6, 2008].MARCH 2009 2. Buono D. IMS study finds decline in prescription drug market growth. Drug Store News. (April 21, 2008) [Available at:; Accessed July 30, 2008]. Dr. Kadriye Çiftci is Senior Director of Drug 3. Lawrence S. Billion dollar babies-biotech drugs as blockbusters. Nature Biotechnol. 2007;25(4):380-382. [Available at: ; Accessed August 6, 2008]. Delivery/Formulations at ICON Development 4. FDA Guidance for Industry M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals. Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research (CBER), (July 1997). Solutions. She has more than 15 years of 5. 2008 Report: Medicines in Development for Cancer. [Available at:; Accessed July 27, 2008]. experience in academia and pharmaceutical R&D. 6. 2007 Report: Medicines in Development for Heart Disease and Stroke. [Available at:; Accessed July 27, 2008] Dr. Ciftci completed her training at the University ofSPECIALTY PHARMA 7. FDA Guidance for Industry M4: The CTD- Quality Questions and Answers/Location Issues. CDER & CBER, (June 2004). 8. FDA Guidance for Industry M4: The CTD- General Questions and Answers. CDER & CBER, (December 2004). 9. FDA Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Illinois at Chicago and the University of Michigan Therapeutic, Biotechnology-derived Products. CDER & CBER, (November 1995). Medical School. She previously worked as a Tenure- 10. FDA Guidance for Industry: INDs for Phase 2 and Phase 3 Studies. Chemistry, Manufacturing, and Controls Information. CDER, (May 2003). 11. FDA Guidance for Industry: Applications covered by Section 505(b)(2). CDER (October 1999). track Assistant Professor at Temple University and a 12. FDA Guidance for Industry: Coronary Drug-eluting stents- Nonclinical and clinical studies. Center for Devices and Radiological Health (CDRH) and CDER (March 2008). Research Fellow at the Schering Plough Research 13. FDA Guidance for Industry: Q8 Pharmaceutical Development. CDER & CBER (May 2006). Institute. Her special interests include cancer 14. FDA Guidance for Industry: Fast Track Development Programs- Designation, Development, and Application Review. CDER & CBER (January 2006). 15. Dagher R, Johnson J, Williams G, Keegan P, Pazdur R. Accelerated Approval of Oncology Products: A Decade of Experience. J Natl Cancer Inst. 2004;96(20):1500- research, gene therapy, and the development of 1509. novel drug delivery systems, particularly biotech72 products and vaccines.