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1、 1 The CRO Market Outlook to 2016 Emerging markets, leading players, and future trends Reference Code: BI00046-006 Publication Date: November 2011 2 About the author Alison Sahoo is a pharmaceutical industry analyst with more than 10 years of experience researching the development of medicines and m
2、edical devices. She holds a B.S. in Physics from McGill University and an MBA in International Business from Rutgers University. Alison has written for Scrip Business Insights on a range of outsourcing and pharmaceutical strategy topics including R these determine what pharmacologic properties a dru
3、g has and which body systems the drug will affect toxicology studies that aim to identify any adverse chemical effects of the drug on the body reproductive and teratology studies that evaluate the effects of individual drugs on reproductive activity, fetal development, lactation and postnatal neonat
4、al development in animals. On average, pre-clinical studies take six years to complete. Initial studies are conducted in vitro and later- stage investigations are performed in animal subjects. Some of these studies may also be performed simultaneously with clinical testing, as non-clinical services,
5、 if study leaders seek further data in particular areas. In general, the goal of pre-clinical testing is to “fail early, fail cheap”, so that inappropriate drug candidates can be identified and eliminated before large amounts of money are spent evaluating them in humans or expensive safety issues ar
6、ise after they are commercialized. However, much still needs to be done in this area, since about 25% of the more than $1.2bn total cost to develop a new drug could be saved through better pre-clinical screens that boost clinical success rates. At present, 250 pre-clinical candidates are typically r
7、educed to five Phase I clinical candidates, of which one will become a commercialized drug. If pre-clinical efficiency were improved, significant resources could be saved by screening out inappropriate candidates earlier. The IND was established by the 1962 Kefauver-Harris Amendment to the Federal F
8、ood, Drugs adults between the ages of 19 and 64 use 10 prescriptions per year and senior citizens age 65 and over use more than 28 prescriptions annually. Biosimilars Biosimilars, also known as biogenerics and follow-on biologics, are officially approved new versions of innovative biopharmaceutical
9、products, following patent expiration. Unlike small-molecule drugs, biologics generally exhibit high molecular complexity, and may be very sensitive to manufacturing process changes. Since the follow-on manufacturer does not have access to the originators molecular clone and original cell bank, nor
10、to the exact fermentation and purification processes, it is often challenging for biogeneric manufacturers to consistently produce good copies of biological molecules. This is particularly true since even very small differences in purity and/or breakdown products can have serious health implications
11、. This has created a concern that copies of biologics might perform differently than the original branded version of the drug. As a result, new versions of biologics are not authorized in the US or the European Union through the simplified procedures allowed for small molecule generics. In the EU a
12、specially-adapted approval procedure has been authorized for certain protein drugs, termed “similar biological medicinal products“. This 30 procedure is based on a thorough demonstration of comparability of the new product to an existing approved biological. The EUs development of such an approval p
13、rocedure and the historic lack of a corresponding regulatory pathway in the US - has led to a growing number of approved biosimilars in Europe. As shown in Table 4. As of mid 2011, 10 generic biologicals have been approved in Europe and just one has been introduced in the US. However, the Approval P
14、athway For Biosimilar Biological Products, passed in early 2010 as part of US health care reform as discussed in the following section, provides such a pathway and is expected to result in a growing number of US biosimilar product launches over the next several years that will challenge branded prod
15、ucts. Table 5 shows expected new biogeneric product introductions in both the US and Europe. Table 4: Biosimilars approved in the US and EU, 2010 Drug Company Indication Region EPO Sandoz, Hospira, Hexal, Medice, Stada Treatment for renal anemia (dialysis patients) and patients with chemotherapy-ind
16、uced anemia Europe Filgrastim Sandoz, Teva Prevention of infection in cancer patients Europe Interferon alfa 2b Teva Treatment for hepatitis C Europe Somatropin Sandoz, Biopartners (EU only) Treatment of human growth hormone deficiency in children and Turner syndrome Europe, US Source: Company filin
17、gs BUSINESS INSIGHTS In anticipation of these changes, and to diversify their operations, several major drug developers have announced initiatives to enter the biosimilars business. In late 2009, for example, Pfizer announced that it was planning to sell copies of biologic blockbusters including Amg
18、ens Epogen and Sanofis Lovenox in four 31 or five years and that its biosimilar pipeline could eventually include 10 to 15 products. To meet these goals, Pfizer is searching for new partners and/or acquisitions. Table 5: Expected biosimilar launches in the US and EU Drug Company US launch EU launch
19、Recombinant human growth hormone Valtropin for the treatment of human growth hormone deficiency in children and Turner syndrome Biopartners GmbH 2013 Available Alpheon (Interferon alfa) for treatment of chronic, active hepatitis C and for certain cancer indications Biopartners GmbH 2014 2012 Interfe
20、ron Beta for the treatment of relapsing- remitting multiple sclerosis Biopartners GmbH 2014 2012 Erythropoietin (EPO) for the treatment of anemia due to renal failure and chemotherapy induced anemia Biopartners GmbH 2014 2012 Ravanex (Ribavirin)for the treatment of chronic, active hepatitis C Biopar
21、tners GmbH 2014 2012 Enoxaparin (Lovenox) anticoagulant for deep vein thrombosis Momenta Pharma 2013 2012 EPO (Eprex) treatment for renal anemia (dialysis patients) and patients with chemotherapy-induced anemia Hospira 2012 Available EPO treatment for renal anemia (dialysis patients) and patients wi
22、th chemotherapy-induced anemia Stada n/a 2011 Filgrastim for prevention of infection in cancer patients Stada n/a 2011 Filgrastim for prevention of infection in cancer patients Sandoz 2011 Available EPO treatment for renal anemia (dialysis patients) and patients with chemotherapy-induced anemia Sand
23、oz 2012 Available Filgrastim for prevention of infection in cancer patients Teva 2011 Available Interferon alfa 2b treatment for hepatitis C Teva 2012 Available Source: Company filings BUSINESS INSIGHTS Escalating R however, broad layoffs can also significantly undercut the research groups productiv
24、ity by removing critical talent and expertise which can be very difficult to regain when the drug developer then wants to scale up its R if not fulfilled the MA may be immediately revoked or suspended implementation of Additional Safety Monitoring for new products for 5 years post-license - monitori
25、ng status will be designated by a black symbol on the products labeling and/or packaging and a statement “This product is subject to additional safety monitoring” in the SmPC and PIL. The legislation also includes significant requirements for pharmacovigilance such as the: appointment of a Qualified
26、 Person who must “reside and operate” within the EU, although Member States may request a national nominated person for pharmacovigilance who should report to the EU Qualified Person for Pharmacovigilance (QPPV) maintenance and availability of a Pharmacovigilance System Master File. This will replac
27、e the Detailed Description of Pharmacovigilance System (DDPS) and is the only summary to be submitted with a Marketing Authorization Application (MAA) creation of a master file describing the pharmacovigilance system including the organization structure including QPPV, Deputy QPPV and national nomin
28、ated persons, risk assessment and management such as how to monitor the outcome of risk minimization measures, communication to patients and a 38 quality system that covers audit, performance indicators, resource modeling, compliance management and records management requirement that the Marketing A
29、uthorization Holder (MAH) regularly conduct audits and keep a note of findings on the Master File. Major changes have also been made to safety reporting such as: an amendment to the definition of Adverse Reaction to clarify that this also applies to medication errors, use outside licensed indication
30、, misuse and abuse a requirement to report all serious ADRs to Eudravigilance within 15 days and report all non-serious EU ADRs to Eudravigilance within 90 days PSURs will be subject to even more changes including: a requirement to submit PSURs electronically a removal of requirement to submit PSURs
31、 for many established products (list to be published) access to data and documents submitted electronically for inspectors, which may reduce pre-inspection requests specification in the MA of the frequency with which PSURs are to be submitted; for MAs granted prior to the implementation of this legi
32、slation, in general, the frequency will be as stated in current legislation ability of MAHs to submit requests to adjust the submission frequency e.g. to aid harmonization requirement for MAHs to submit to EMA PSURs containing summaries of data relevant to the benefits and risks of the product (line
33、 listings will no longer be routinely required), data on sales as well as prescriptions and comparison of real world use to indicated use, Signal and Risk Evaluation (ineffectiveness of risk minimization), Benefit Evaluation (efficacy this will also apply to final study reports and abstracts allowin
34、g PRAC to make recommendations concerning the terms of the MA based on the results of safety studies providing more oversight of safety studies. As of late 2011, however, little guidance has been issued pursuant to the complicated new rules. While the legislative implementation measures and Good Pha
35、rmacovigilance guidelines are currently being drafted, many modules are not expected to be completed prior to July 2012 and changes to Eudravigilance are not expected until at least January 2016. Many drug makers, even those with large legal and compliance teams, are unclear on the exact nature of t
36、he changes they will have to make to fully comply with the new requirements. Drug developers with less expert regulatory staff continue to struggle, and are expected to rely heavily upon third party contractors and consultants (including CROs) who can help them navigate the new regulatory landscape.
37、 Heightened regulatory scrutiny In recent years, regulators in both the US and EU have intensified their efforts to ensure the safety of approved medicines. This encompasses both more stringent pre-approval evaluations, often marked by more frequent and detailed requests for additional data, as well
38、 as requiring a greater number of post- marketing studies for approved medicines. 40 In the US and EU, 75% of new drugs approved between 1998 and 2010 had post-marketing commitments, according to the Tufts Center for the Study of New Drug Development, with the average number of post- marketing studi
39、es per drug ranging from 10.8 in the EU to 8.9 in the US Particular areas of interest in post marketing studies include the effects of the drug on special populations such as minorities, children, seniors and individuals with specific conditions. The regulators have also become more active in seekin
40、g market withdrawals for approved products with demonstrated safety risks; for example, the FDA recently recommended a ban on prescription painkillers Vicodin and Percocet due to concerns about the effect of high doses of acetaminophen on the liver. Two areas in which FDA scrutiny is likely to furth
41、er increase are clinical trial investigator sanctions and post marketing studies. In September 2009, the GAO issued a report on the FDAs disqualification of clinical trial investigators who have engaged in misconduct such as submitting fraudulent data. The GAO found that since 1992, more than half o
42、f the debarment proceedings took four or more years to complete due to internal control weaknesses in the debarment process and competing priorities among agency staff. FDA made changes to its disqualification process by establishing procedural time frames in June 2008 and January 2009, but the effe
43、ct of these changes remains to be seen. It is therefore not unlikely that the FDA will continue to tighten its processes in this area. The GAO also found that FDA had not followed up with required post-marketing studies for drugs approved on the basis of surrogate endpoints (laboratory measures, suc
44、h as blood pressure, rather than direct clinical evidence, such as the ability to prevent stroke). FDA approved 90 accelerated applications for high priority drugs with surrogate endpoints between 1992 and 2008, requiring 144 associated post-marketing studies; as many as one third of these have not
45、yet been completed. FDA also approved another 69 NMEs on the basis of surrogate endpoints, requiring 175 post- marketing studies; only half of those have been completed. Additionally, the FDA is increasingly requesting additional data before even a preliminary review. In November 2009, for example,
46、the agency refused to accept Mercks application for a new combination cholesterol pill combining Pfizers Lipitor with Merck and Schering-Ploughs Zetia, requesting further information on manufacturing and stability of the drug. The refusal is unusual and underscores the FDAs 41 increasing caution, pa
47、rticularly as the application pertains not to a NME but to a combination of two approved molecules and the FDA has approved similar products such as Mercks Vytorin (Zetia combined with simvastatin). Similarly, in early 2011 the FDA voted against approving Genentech/Roches Avastin for treatment of br
48、east cancer, although the drug is approved in Europe for this indication. The EMA is also re-focusing on patient safety. In May 2009, the agency announced a reorganization that would bring together all groups responsible for the evaluation of human medicines. At the same time, a new division called
49、Patient Health Protection was created to combine and enhance the EMAs pharmacovigilance, risk and crisis management, patient and health care professional information, inspections and regulatory compliance functions. Decreasing drug approvals Rising regulatory scrutiny is resulting in a declining number of new drug approvals. This is particularly troubling in the context of an increasing number of clinical trials and escalating R in Europe, however, they tend to include more generalist mid-cap investors who are less well acquainted with the unc