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Designing Clinical Trials for Market Access
| 작성자 | 관리자 | 카테고리 | 전문가 인사이트 |
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| 작성일 | 2016-05-30 | 조회수 | 1,740 |
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Designing Clinical Trials for
Market Access
- 글 Robert Freeman
- GPKOL 위원
상임 컨설턴트
컨설팅 분야
- 생산(GMP): API 생산
- 임상, PM
주요 약력
- 2012-현재 The University of Maryland Eastern Shore, Professor and Vice Chair of Research
- 2008-2010 Texas A&M Health Science Center, Director of Graduate Studies
- 1998-2005 AstraZeneca Pharmaceuticals, Executive Director
Robert Freeman, PhD, Professor and Vice Chair of Research, Department of Pharmacy Practice & Administration, The University of Maryland Eastern Shore School of Pharmacy, Princess Anne, Maryland 21853, USA, email rafreeman@umes.edu
Based on a presentation at the 5th GPKOL International Symposium, Korean Health Industries Development Institute, 2016 BIO Korea, Seoul COEX Korea, March 31, 2016
Introduction
Entering the USA market is relatively straightforward. The US Food and Drug Administration (FDA) requires two well-controlled randomized clinical trials to determine safety and efficacy for a new chemical entity (NCE) or biologic. For oncology drugs and other new NCEs and biologics that treat life-threatening diseases conditional approval may be granted after proof of concept and safety are established in Phase II trials; however, proof of safety and efficacy must be established in Phase III trials for approval to be final. The approval process generally takes a number of years, and the FDA can request additional information at any point in the review process.
At the end of the approval process, the company negotiates final labeling (approved indications, dosages, safety warnings, etc.) with the FDA. The US FDA is under pressure from patient groups and the government to speed up the new drug approval process. While drug approval times are becoming shorter for some drug classes, recent incidents of drug safety problems have been noted, and the FDA is increasing the emphasis on post-approval drug safety studies. These Phase IV safety studies are often required as a condition in the drug approval decision and must be undertaken and reported to the FDA at completion.
The FDA does not comment on pricing; rather, the company is free to set its launch price without government involvement. Transaction prices between the pharmaceutical company and its customers occur in the private market and are determined by contractual negotiations between the company and private third-party payers. These prices are considered trade secrets and are not disclosed by either party. Public third-party payers (Medicare, Medicaid and the Supplemental Children’s Health Insurance Program—sCHIP—do not negotiated prices or reimbursement. (The only exception to non-government intervention is the US Veterans’ Administration (VA) and the Department of Defense (DOD). These governmental organizations purchase drugs (patented and generic) directly from the manufacturer and require the seller to offer its “best price”, a price point below which the drug cannot be sold to any customer in the private market.)
Securing FDA approval does not automatically ensure commercial success. Private and public third-party prescription drug payment programs typically place market access barriers such as drug formularies comprised of formulary tiers, prior authorization programs, financial incentives favoring preferred patented drugs or generics, and step therapies to control the use of NCEs and specialty drugs (biologics). Additionally, payers want to see comparative effectiveness of new drugs in relation to a recognized drug of choice, or standard. These types of studies are seldom available at market launch, and widespread formulary inclusion is retarded until comparative outcomes are available. It can be assumed that specialty drugs (those with annual costs exceeding $5000 or more) will be managed aggressively by specialty drug benefit management companies that will restrict the use of the new drug to only those patients who are likely to receive positive clinical outcomes.
Market access to NCEs and biologics is essential because revenue losses that occur due to delayed third-party payers’ coverage decisions (drug formulary decision-making) can never be recovered. The importance of strategic planning in the clinical development program cannot be overstated: a robust portfolio of Phase III-b and Phase IV clinical studies is absolutely essential to market success. If planned and executed properly, initial comparative clinical studies can be available before and immediately after launch to present to private third-party payment programs. It is important to note that comparative trials, in this sense, involve the design of studies that reflect the “real world” use of the need drug in comparison to existing therapy and have less rigid enrollment requirements as do randomized, controlled clinical trials.
The Current Environment for Clinical Trials and Studies
As noted, the gold standard for regulatory approval of a NCE or biologic is the well-controlled, randomized clinical trial. In some instances, this means comparing the new drug to a placebo. In other instances, an active control (the current therapeutic choice) can be used instead of a placebo. In these cases, an active control overcomes ethical concerns of withholding care from a patient with a life-threatening disease, and an active control is also preferable in therapeutic classes when an established treatment of choice exists. These types of trials have long-term credibility with the FDA as meeting its criteria for establishing safety and efficacy.
Drug companies may either use an equivalency trial or a non-inferiority trial when sufficient evidence of the effect size exists to set the null hypothesis of non-inferiority. Adaptive clinical trials are also becoming more common, but caution should be exercised to ensure that an adaptive trial is acceptable to the FDA. Briefly, an adaptive trial designs are beyond the scope of this report, and the reader is referred to Zang and Lee (2008) and the FDA Draft Guidance (2010). The trials are especially useful in oncology trials, minimizing study population requirements, dosage adjustments and in other therapeutic area to identity patient subgroups where the NCE or biologic appears uniquely effective. They are not without controversy; however; and the FDA must agree to criteria to modify the trial while it is still in progress.
Perspectives about Primary and Secondary Clinical Trial Endpoints
Primary and secondary endpoints for clinical development of most therapeutic areas are generally well-known and accepted by the FDA. “Hard’ clinical endpoints are those therapeutic outcomes that have direct meaning in the treatment of a disease and represent the primary endpoints of the clinical trial. They will determine sample size of the treatment and control groups, the statistical power, and guide the estimation of effect size differences when an active control is used. The inclusion of secondary endpoints is becoming increasingly common in Phase III clinical trials. The reasons underlying their inclusion are sometimes outside the classic definition of clinical efficacy outcomes. Hospitals and physicians are under increasing pressure to achieve outcomes that result in lowing the risk of readmissions to hospitals in 30-day post-discharge as well as other outcomes that are associated with healthcare resource utilization and costs. As a result, variables that are related to these outcomes are often included as secondary endpoints. It should be noted; however, that statistically significant differences in these outcomes between the “control’ and the “experimental” cohorts are difficult to achieve because the study’s power calculations are based on differences between the primary outcomes. It is also fairly common to include health-related quality of life outcomes as either primary or secondary outcomes because these variables may have meaning to patients and prescribers.
As a caution, the pharmaceutical company must use validated and reliable instruments that are general and disease-specific to satisfy the FDA. Unfortunately, all things being equal, US public and private payers do not weigh these findings positively in drug coverage decision.
For studies conducted after the NDA is filed, it is common to find pharmaceutical companies conducting clinical studies (randomized and non-randomized) using resource utilization and costs as key variables to influence formulary decision-making positively. These studies are typically not used to secure additional clinical indications for the new drug; rather, they are intended to provide “real word” evidence about the drug’s use in actual medical practice.
Randomized Clinical Trials and Comparative or “Real World Evidence” Clinical Studies
The very strength of the randomized clinical trial is that it is the best research design to ensure internal validity. Unfortunately, it is difficult to generalize the results from clinical trials to other patient populations. Inclusion criteria for patients is tightly controlled in that patients with significant co-morbidities are excluded; pregnant women or women who may become pregnant are excluded; subjects under 18 years of age are excluded as are subjects over 75 year of age; and ethnic minorities are underrepresented. Drug dosages are defined by the drug dosing studies and patients must comply with protocols that specify a series of physician visits and laboratory testing that would not be evident in actual medical practice. Moreover, the use of a placebo or a regulatory-determined standard of care (the active control) with prescribed doses does not reflect how the new drug will be used in practice. For these reasons, third-party payers are skeptical about the initial evidence and insist that follow-up studies be performed with “real patients” in private practice to get a better understanding of the drug’s effectiveness as opposed to its efficacy as determined in an artificial clinical trials environment.
As a result, the literature contains numerous examples of comparative outcomes studies, also known as “pragmatic trials, outcomes research trials, comparative effectiveness trials, patient-reported outcomes, all of which have the objective of providing information upon which payers prefer to make coverage (formulary) decisions. As noted, non-inferiority trial designs are frequently used to undertake the comparison. It is rare; however, to see superiority trials used because of the difficulty in estimating true effect size differences between two active drug. As a general rule, it is advisable to conduct primary research with key decision makers in third-party programs to guide the design of “real world” trials. Also, instead of prospective clinical studies, retrospective cohort studies (new drug in comparison to established drugs) of the new drugs in specific at-risk populations are quite common, despite the limitations of these designs.
Costs of Clinical Development Programs (USA estimates, 2011)
For the most part, research-intensive pharmaceutical and biologic companies do not disclose clinical development costs for specific drugs, preferring instead to report aggregated R&D expenditures for a current year. There is no requirement that they do, and the reluctance to disclose costs at a granular level is due to the intense competition for research sites (prestige) and research clinicians (key opinion leaders in a therapeutic area). The best estimate of developmental costs comes from the firm MediData Solutions, which broke down clinical research costs by therapeutic area and phase of development. Their findings are displayed in Tables Ia, Ib II, III, and IV.
As seen in Tables Ia and Ib, considerable variation exists amongst therapeutic area. In some areas (pain, e. g.) multiple measures of pain are required, and a strong placebo effect requires large sample sizes to detect significant differences. At the other end, antibiotic development has “clean” endpoints (“cure”, partial cure, failure) that are captured in a finite number of days.
The information in Table II and III reveals that developmental costs, as expected, as the NCE or biologic progresses successfully from one Phase to another. Somewhat surprisingly, Phase IV (post-marketing safety studies) now equal Phase III development costs, most likely due to the FDA’s increasing emphasis on long-term safety outcomes in very large patient populations. As noted, some of the highest costs are incurred in oncology, again due to the emphasis on long-term patient survival required by the FDA.
Table V contains a breakdown of the total costs of clinical drug development by type of expenditure. Independent from the one-year data presented in Table V, one of the strong trends in the cost of drug development is the increasing cost of site recruitment and retention. Again, the costs are highly variable by therapeutic class and the reader is referred to the MediData Solutions report for detailed information.
A Summary of Key Trends in Clinical Development
The basic costs and time of securing FDA approval of NCEs and biologics are increasing, and drug development is shifting into more attractive areas, notably drugs for rare and ultra-rate conditions and to the treatment of chronic medical conditions that have large patient populations and unmet medical need. Obviously, oncology drugs and drugs that treat life-threatening conditions remain attractive commercial products given shorter development times and expedited approval. As noted, the need to plan Phase III trials that reflect real world experience is now expected by third-party payers.
Strategic Planning of Clinical Development Programs to Address Market Access Needs
Market access can be facilitated if these types of clinical studies are considered as integral parts of a total clinical development program. Ideally, at least a portion of these studies should be available for presentation to private third-party programs with six months pre-and post-launch and after pricing has been set for the NCE or biologic. Suggested clinical trials include the following:
- Pragmatic or “real world” clinical trials are studies that are collected on a broader group of patients than those enrolled in traditional clinical trials. Study subjects are not subjected to strict protocols, monitoring and dosing regimens. Patients reflect those found in actual medical practice.
- Physicians and patients are aware of drugs under study. Double-blinding is typically not used, although single-blinded studies are commonplace. These are called “open-label” studies and under the supervision of the Medical Affairs Division.
- Pragmatic studies typically involve several thousand patients who are evaluated prospectively.
- Patient-reported outcomes measuring patient satisfaction and symptom relief are typically included. Validated and reliable instruments specific to the therapeutic area are strongly recommended.
- Pragmatic studies in early development involves mining genomic data for markers that predict use across indications.
- Pragmatic trials and patient-reported outcomes address payer needs for value but not regulatory bodies’ criteria for marketing approval
Although the emphasis of this paper so far has been in Phase III, III-b and IV, “real world evidence” can be collected across the development process. For instance, the identification of biomarkers that may be related to expanded indications can start in Phases I and II. Upon identification, biomarkers can be linked to electronic medical records to predict patient groups that may respond to the NCE or biologic. Additionally, subgroups can be further described for both safety and efficacy based on the presence of biomarkers.
The Target Product Profile and Target Value Profile
The Target Product Profile (TPP) reflects the company’s ideal product labeling and the incremental clinical benefit the NCE or biologic possesses in comparison to its current and anticipated competitors. It is a forward-looking statement of the commercial value of the product as measured by its safety and efficacy for one or more indications
More and more companies are developing a complementary profile, the Target Value Profile (TVP) that expressed the incremental value of the N CE or biologic in economic and humanistic (health-related quality of life and patient satisfaction/patient outcomes) terms.
If properly and objectively stated, the TVP can direct the developmental, commercial and regulatory divisions in the strategic planning of either distinct economic and humanistic trails or parallel track trials to existing clinical trials. The best practice is to form an interdisciplinary team of commercial, regulatory, medical affairs, clinical development and market access leaders that has the remit of designing an integrated clinical development programs that includes both basic clinical research and a value proposition.
Conclusions and Recommendations
A successful regulatory approval does not automatically equate with commercial success. A foreign company entering the USA market should plan clinical programs that address requirements of third-party prescription drug benefit companies that, in effect, determine how commercially successful a new product will be.
The following list contains recommendations for Korean pharmaceutical companies entering the USA market for the first time:
Clinical trials that were conducted in Korea exclusively will likely be accepted by the US FDA provided the criteria for two independent well-controlled, randomized clinical trials are met. The best way to determine this is to meet with the FDA in the presence of a well-established legal firm that specializes in FDA regulatory law. Unless there is genetic evidence to suggest that ethnic Koreans are uniquely different in terms of safety and efficacy from other ethnic groups, there is no reason to assume that the trials will have to be replicated in US citizens who have more diverse ethnicity.
Health economic analyses are not required for regulatory approval and only have value if all the relevant information needs of a third-party payer are met. It makes far more sense to plan to conduct budget impact analyses at the specific-payer level using a general model tailored to the customer level. Briefly, a budget impact analysis tells the third-party payer the financial outcomes (profit, loss, breakeven point) as the new drug is adopted and utilized in its patient population.
A great deal of access barriers can be removed post-approval by creative contracting practices with specific payers. Again, comparative safety and efficacy is the most important factor, but willingness to engage in rebating and contracting is essential. This does not mean lowering price but being flexible in creating patient access programs to reduce out-of-pocket costs, offering volume-based rebates that are performance based, and considering risk-sharing arrangements with payers and hospitals.
In summary the USA market is dynamic, complex and fragmented. There is no national health system, and the coverage of drugs is largely a private-sector decision under the prerogative of multiple payers. The market, despite access issues, is pro-innovation and new products with clear clinical and economic advantages will be successful. Fortunately, the FDA is transparent in its decision-making and treats foreign and domestic firms with equity.
References:
- Shein-Chung Chow and Mark Chang. Adaptive design methods in clinical trials-a review. Orphanet J Rare Dis. 2008 May 2. doi: 10.1186/1750-1172-3-11.
- US Food and Drug Administration. Guidance for Industry: Adaptive Design of Clinical Trials for Drugs and Biologics. (2010) http://www.fda.gov/downloads/Drugs/.../Guidances/ucm201790.pdf
- A Sertkiva, HH Wong and I Beleche. Key Cost Drivers of Pharmaceutical Clinical Trials in the US. 2016. Clin Trials. (13) 2:117-26;
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