	There seems to be a general agreement among policymakers and in the research community that the Food and Drug Administration (FDA) has done about as much as it can to speedily review and approve important new therapies, and that efforts to facilitate patient access to needed medical products now should focus on accelerating drug development and clinical testing. Thus, the slimmed-down April version of the 21st Century Cures legislation from the House Energy & Commerce Committee (E&C) backs a number of strategies for modernizing and simplifying clinical trials, incorporating patients’ voices into product development, encouraging collaboration on biomarker qualification, and reducing waste and redundancy in the clinical research process.

	Under that last heading fall proposals to promote the use of central institutional review boards (IRBs). The legislation authorizes “lead IRBs” to oversee multi-site human subject research, specifying that cooperative research projects could establish a joint or shared review process or utilize an independent IRB; FDA guidance would address the need to incorporate local community values when central IRBs are used.

	Another efficiency provision would exempt FDA-regulated clinical trials from also meeting requirements set by the Common Rule. And Congress looks to make it easier for patients to access clinical trial information on the ClinicalTrials.gov website by standardizing data and formats. Even though FDA already is doing much to accelerate biomarker qualification and use of Bayesian statistics and adaptive trial designs, there’s general support for language in the bill emphasizing Congressional support for such efforts.

	Several research-related provisions, though, raise red flags. There’s considerable concern about a proposal permitting sponsors to waive informed consent for clinical investigations of drugs and medical devices that pose “no more than minimal risk” to participants. Even though sponsors would have to take “appropriate” steps to protect the safety and welfare of subjects, patient advocates fear this would undermine usual patient safeguards.

	Also controversial are research “modernization” proposals with potential to radically alter the biomedical development process. One would authorize greater use of “real-world evidence,” with language requiring FDA to approve certain new indications based on “clinical experience” data from registries and from FDA’s Sentinel System. Another aims to reduce the volume of clinical data supporting market applications by permitting manufacturers of approved drugs to submit “qualified data summaries” in efficacy supplements to gain approval of a “qualified indication.” FDA guidance would clarify this “streamlined data review” system and the types of indications eligible for the program, but critics warn it will undermine usual assurances of drug safety.

	As the legislators rolled out their bipartisan draft proposal last month, FDA officials voiced concerns about just how these initiatives would be crafted and implemented, and where the agency would get the resources needed to carry out its many requirements. House leaders authorized a significant budget increase for the National Institutes of Health (NIH), but gave FDA less than $100 million a year to modernize trial design and evidence development. More important is a provision exempting FDA user fees from budget sequestration. 

	Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), stated at a hearing before the E&C health subcommittee in April that a new law requiring new programs and multiple guidances could undermine her ability to meet review and approval commitments. This latest E&C proposal has “significant resource implications for FDA,” she said, noting that CDER’s new drug review process is now “going at full speed, and we’d like to keep it that way.” Getting new therapies developed efficiently is helped by timely advice from the agency, and that “would be the first to go,” she warned, if the agency gets further stretched on resources.

	What FDA sorely needs, Woodcock and other agency officials emphasized, is to cut some of the red tape and obstacles to bringing in the experts able to address complex scientific and regulatory issues. Too-low salaries prompt experienced staffers to leave for more lucrative jobs in industry and academia, and complex government employment requirements make it hard to recruit top talent.

	To gain Democratic support for the Cures proposal, Republicans dropped earlier proposals to extend exclusivity on certain innovative drugs and improved formulations. With time now running out to negotiate other contentious issues, the legislators may agree to enact a much smaller “Cures” bill this year: the short list includes further biomarker qualification, a breakthrough program for medical devices, flexibility on communicating drug economic information, broader use of central IRBs, and development of “limited use” antibiotics. There would be more money for NIH, but Congressional appropriations committees will have the final say on funding levels. The rest of the FDA reform items then would be held for further discussion and possible incorporation into user fee legislation in two years.

Articles

News

Agency concerned about how proposals in "Cures" bill will be crafted and implemented.

FDA Seeks Resources to Support New Research Initiatives

	Biologic drugs and non-biologic complex drugs (NBCDs) have revolutionized the treatment of many difficult-to-treat diseases including cancer, multiple sclerosis, and chronic iron deficiency. Biologic drugs are derived from living sources, such as microorganisms. NBCDs are produced by chemical synthesis, rather than from a living source; however, like many biologic drugs, the active ingredients in NBCDs typically comprise complex heterogenous (but closely related) nanomolecular components that cannot be isolated, fully quantitated, or completely characterized–even when using state of the art physicochemical analytical tools. Additionally, NBCDs may have multiple or unknown modes of therapeutic activity.

	Patents for many biologics and NBCDs are soon expiring and drug manufacturers are actively working

 toward producing biosimilar drugs and follow-on versions of NBCDs. The FDA has issued three final guidances for development of biosimilars based on feedback from pharmaceutical and biotech companies, researchers, and patient and physician groups. On March 6, Zarxio (filgrastim-sndz) became the first biosimilar product to receive marketing approval from FDA. Currently, no FDA guidance is available regarding regulatory requirements to ensure the safety and effectiveness of follow-on versions of NBCDs. While nonbiologic, small-molecule, generic drug approval is based on long-established, clearly-defined regulatory requirements, regulators must carefully consider the applicability of “pharmaceutical sameness” to follow-on NBCDs as their regulatory approval pathway is defined.

	Generic drugs cost less than branded drugs because their approval does not require clinical testing. In the classic approach, a generic drug must be shown to have an active ingredient that is identical to that of the reference drug and to have the same mechanism of action. However, in the case of NBCDs, two drugs cannot be shown to have identical active substances if the active substance has not been fully identified, nor can they demonstrate the same mechanism of action if it remains unknown or not fully elucidated. Importantly, the identity and quality of NBCDs are contingent on their well-controlled (often proprietary) manufacturing process. Follow-on NBCDs that are manufactured differently from the original branded product could have minute structural or compositional differences from the original product that are undetectable but might compromise product safety.

	Despite these caveats, the FDA has accepted abbreviated new drug applications for follow-on NBCD products. This concerns many physicians and other medical experts because a follow-on NBCD may have difficult-to-detect differences from the original drug that cause serious safety problems that only come to light after the drug is marketed. Concern is amplified for physicians who treat patients with chronic autoimmune diseases such as multiple sclerosis, in which a slight change to a previously successful immunogenic therapy could prompt serious adverse events or compromise long-term effectiveness.

	To ensure the safety and quality of follow-on versions of NBCDs, FDA should require Phase III clinical trials with relevant safety and efficacy endpoints. Further, once follow-on NBCDs are available, comprehensive post-marketing surveillance and risk-assessment programs should be in place to capture drug side effects that may not be evident in 1- or 2-year clinical trials. 

, MD, is Global Senior Medical Director for Multiple Sclerosis, Teva Pharmaceuticals 

A Closing Thought

With patents for many NBCDs soon to expire, the need for regulatory guidance regarding follow-on versions of these products is crucial.

Safety Considerations for Follow-On Non-Biologic Complex Drugs

	There is plenty to read in the European Medicines Agency's (EMA) just-published annual report for last year. But much of the attention of the clinical trials community will be directed to checking just how far this rather routine publication reflects a very new and very recent trend towards candor in the agency.

	The sheer volume of the information in the annual report is, itself, remarkable, because the agency now has so many tasks reaching into so many corners of the world of pharmaceuticals. The report covers the core activity of recommending human-use medicines for European Union (EU) marketing authorization (82 in 2014)-and not all of these were routine, either. The year saw the first recommendation of a medicine for the treatment of Duchenne muscular dystrophy, the first treatment for erythropoietic protoporphyria, and the first therapy based on stem cells. Overall, 17 of the medicines that got the green light from the EMA were intended for the treatment of a rare disease-a new record.

	It also covers the currently contentious subject of early EMA scientific support for companies developing medicines (health campaigners are claiming that it carries a risk of conflicts of interest), where the number of requests in 2014 set a new record, with three-quarters of applicants benefiting. The report notes the use of accelerated assessment procedures for medicines expected to be of major benefit for public health (seven positive opinions were granted through this route, including for four new-generation medicines for treating chronic hepatitis C virus (HCV) infection, led by Sovaldi). And it covers the equally contentious subject of transparency-with the EMA's adoption of its new policy on the publication of clinical data, the widening of the European database of suspected adverse reactions, its publication of agendas and minutes for the meetings of all its scientific committees.

	New responsibilities are also reported on-with additional tasks imposed by the implementation of new EU legislation on pharmacovigilance (and, in 2014, new fees charged to industry for this increased monitoring)-falsified medicines (including producing new guidance for good manufacturing practice and good distribution practice inspections), and on clinical trials (creating the portal and database to be used for submitting applications for trial authorization).

	So much for the routine. But of greater interest is the tone adopted for discussion of the quality of the agency's work.

	"The European medicines regulatory network is the cornerstone of the work and success of the agency," it says, pointing to the "experts from national authorities carrying out the assessment of medicines on behalf of EMA." It goes on to comment that "to be able to carry out the work to a high level of quality, it is essential that more and more national authorities participate in the assessment of medicines."

	The urgency in the expression of this ambition coincides with the message at the heart of a major strategy document that EMA published shortly before its annual report. "Regulatory capability varies across the network. Some national competent authorities have more expertise in certain areas than others," says "Network Strategy to 2020," a 25-page consultation document that clearly recognizes weak links among the member states. This document-which is open for comment until June 30, and describes itself as a "draft strategic vision"-insists: "The network must ensure that all national competent authorities that participate in a specific type of regulatory activity continue to have the capability to do so. A critical success factor for the network will be to have available and at its disposal sustainable high-quality scientific and regulatory expertise able to address progress in regulatory science."

	In other words, right now, there isn't enough capacity, and what there is, is not always adequate to the task. The need exists, continues this consultation document, for "a clear identification of any gaps in scientific and regulatory expertise based on current and future needs, and a corresponding competence development program," as well as for "common standards of scientific quality across the EU regulatory network," and for strengthened output, "in particular the scientific quality of regulatory processes," to "mitigate discrepancies within the network."

	The point was made very tersely by Professor Sir Alan Breckenridge, who told this columnist during the reception to celebrate the 20th birthday of the EMA: "The problem with the EMA is that there are 28 members but the contributors are about six. This is something that's got to be worked on, because there's huge variability in expertise across the whole of Europe. This is a real problem-because when it comes to a decision, all of the agencies have a vote, but about 20 of them don't have an idea of what they are voting on."

	The problems-in many cases longstanding-have come to the surface because of the new challenges that drug regulators and drug innovators are facing. As EMA puts it, a new framework is needed to tackle new science and new economic constraints, and to find radical new responses to cater adequately for the health of Europe's citizens. New technologies, the changing nature of pharmaceutical innovation, new advanced therapies, new licensing pathways and product life-span approaches, greater use of real-world databases, the increasing globalization of the pharmaceutical industry, and new and emerging health threats-whether in the form of antimicrobial resistance or emerging epidemics, as demonstrated by the outbreak of Ebola, or through criminal activity such as falsification of medicines. It is important, EMA believes, that the network keeps abreast of these advances to ensure that novel products can be developed optimally for the benefit of the health of the citizens of Europe.

	The annual report takes a more modest approach to this challenge than does the EMA strategic vision-or Sir Alastair. It says there is "an important positive trend for the EU system," in that "efforts undertaken during the last few years are paying off." One positive factor is that more national authorities are becoming involved in EMA procedures as rapporteurs or co-rapporteurs (up from 16 in 2010 to 24 in 2014). But even the moderately-worded annual report does tacitly admit that more is necessary, and describes how the agency has tried during 2014 "to ensure its continuation," with the launch of initiatives that "aim to better support the assessment work of the many thousands of EU experts involved in the regulation of medicines."

	One of these is the EU Network Training Centre, jointly operated by the EMA and the less formal group of heads of national medicines agencies in the EU. This is building "a training strategy for continuous professional development of staff from national competent authorities and EMA, in order to improve the quality, consistency, and efficiency of the work of the network and promote harmonized application of the regulatory framework and guidelines." Another is a new scheme in which the agency supports the creation of multinational co-rapporteur teams to assess initial marketing authorizations for medicines for human use, "to make use of the best expertise across the EU for the assessment of a marketing authorization application." It follows a successful pilot scheme.

	The pilot involved Denmark, Estonia, Finland, Latvia, Lithuania, Poland, and Sweden, as well as Iceland and Norway (which are closely associated with EMA, even if they are not EU member states). EMA has found it so useful, it is now exploring how the scheme can be extended.

	So two tones are evident as the 20-year-old EMA experiences its epiphany. One is candid to the point of being undiplomatic. The other is more measured. But it is striking that the moderate tone in the annual report belongs to things of the past. The more assertive tone, as in the "draft strategic vision," is very much geared to the future.

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

View from Brussels

The tone of agency’s annual report contrasts its recent candid stance on regulatory vision for Europe

Putting the EMA House in Order

	A new report has urged the global pharmaceutical industry to support an innovation fund to boost research into antibiotics. In return, companies that develop new antibiotics would receive guaranteed payments of between $2 billion and $3 billion.

	The document, “Securing New Drugs for Future Generations: The Pipeline of Antibiotics,” was put together by the Antimicrobial Review (AMR) Committee, a U.K. government-appointed review team headed by Jim O’Neill, the economist and former chair of Goldman Sachs Asset Management. The AMR Committee assessed the development pipeline for new antibiotics, and has made initial proposals for the global action needed to kick-start antibiotic drug discovery efforts. This includes proposals for ways of channeling new money into early-stage research relevant to tackle AMR and for major global interventions to ensure that drug developers can be sure of a predictable and viable market for new antibiotics that can successfully tackle society’s most acute unmet needs.

	“Drug-resistant infections could kill an extra 10 million people across the world every year by 2050 if they are not tackled. By this date they could also cost the world around $100 trillion in lost output, which is more than the size of the current world economy,” noted the authors.

	At the launch of the report, O’Neill stated that a fund worth between $16 billion and $37 billion per decade would be enough to incentivize drug companies to turn their attentions to antibiotics. In an article published by the 

 newspaper in mid-May, he said it was possible the global taxpayer would have to foot the bill for the fund.

	“I’d say, averaged out over 7.2 billion people, it is not that much compared to one million people dying a year in China or India in 2050,” he pointed out. “We need to kick-start drug development to make sure the world has the drugs it needs, to treat infections and to enable modern medicine and surgery to continue as we know it.”

	Resistant strains of bacteria are spreading across the world, threatening to make existing drugs ineffective, and because the empty pipeline for antibiotics is a matter of great importance for every country, O’Neill intends to raise the finance issue at the next G20 meeting. Furthermore, if the pharmaceutical industry is to avoid a damaged reputation from the looming crisis, it must show ‘enlightened self-interest’ by contributing to the scheme, he continued.

	Companies would be rewarded with payments if they successfully launch a new antibiotic, as long as they do not seek to sell the drug at a profit. It would be sold on a not-for-profit basis, or made by a generic company with low overheads at a cheap price instead, as happens in developing countries with drugs for HIV. The global market for antibiotics is currently worth around $40 billion a year, and the prize fund would cost about 10% of that sum, according to the 

	The authors think resistance breakers are a promising area of research. These compounds can boost the effectiveness of existing antibiotics, and this approach is cheaper than attempting to discover totally new drugs. For instance, Helperby Therapeutics in the U.K. has created a resistance breaker that acts against the superbug methicillin-resistant 

 (MRSA). Known as HT61, the compound is due to enter clinical trials in India, where it is being developed under licence by Cadila Pharmaceuticals India. This kind of research could benefit from the innovation fund and may prove vital to making existing drugs last longer, the authors believe.

	It has been nearly 30 years since a new class of antibiotics (i.e., a group of drugs with an entirely novel action) was introduced, according to a recent report by BBC News. But the drought may soon be over as a result of a breakthrough recently announced by U.S. scientists. A team at Northeastern University in Boston has discovered 25 potential new antibiotics, all of them derived from soil microbes. One of them, teixobactin, is effective against both tuberculosis and MRSA. The drug is being developed by NovoBiotic Pharmaceuticals and should go into patient trials within two years.

	“We have to respond to the challenge of antimicrobial resistance by making sure we secure the necessary antibiotics for generations to come, in order to save millions of lives and billions of pounds,” Prof. Dame Sally Davies, chief medical adviser to the U.K. government, told BBC News.

	The AMR Committee’s final report with global solutions is scheduled for publication in the summer of 2016. It is considering how improvements in the following areas can help tackle antimicrobial resistance: the supply of new drugs, rapid diagnostics, surveillance, infection control, alternative treatments, and the use of antibiotics in agriculture.
	
	“AMR is a complex global issue which cannot be solved by any one country acting in isolation. In this regard we think that China has a great opportunity to bring the world together in the fight against AMR when it hosts the G20 in 2016,” wrote the authors.
	
	The report can be downloaded free of charge from the AMR's website, 

Experts Call for Urgent Action on Antibiotics Research

		The opportunity to more precisely target and to personalize medical treatments based on biomarker data has attracted growing interest from biopharmaceutical companies. A recent study by the Tufts Center for the Study of Drug

 Development (Tufts CSDD) finds that oncology dominates personalized medicine product development in part because cancer-related illnesses are extremely complex and they receive the highest level of R&D activity. Companies involved in developing personalized medicines report that across all phases, 73% of oncology drugs now rely on biomarker data. This compares with 42% of compounds in all indications.

Study finds that almost 75% of cancer drug candidates rely on biomarker data. 

Oncology Leads Personalized Medicine

	It is widely acknowledged by professionals involved with conducting clinical studies, as well as by those who oversee and manage clinical trials, that investigative sites face a heavy regulatory compliance burden. Yet, until recently, only anecdotal evidence existed to support this belief.

	CenterWatch, in collaboration with Complion-a Cleveland-based firm that develops regulatory documentation solutions for investigative sites-have completed a new study that begins to quantify this regulatory compliance burden.  

The study was conducted online between October and December 2014. A total of 164 U.S. sites completed the survey questionnaire. The majority of respondents (60%) are study coordinators; 20% are principal investigators. The remainder of respondents includes administrative support and regulatory staff, among other site personnel.

	Nearly four out of 10 (38%) of the respondents work in independent, dedicated, and part-time community based sites. One-third (35%) are based within academic medical centers (AMCs) and 27% are within community hospitals.

	The results suggest that investigative sites are dedicating substantial capacity, infrastructure, and resources to manage regulatory compliance. And the expense to do so dramatically reduces site operating profit. Most sites are handling regulatory compliance tasks in a relatively unsophisticated manner, using a combination of paper and electronic solutions. And sites expect the regulatory burden to increase. What follows are highlights from this recent study.

	The majority (85%) of investigative sites perceive that the burden and cost associated with regulatory compliance has increased “significantly” (41%) or “somewhat” (44%) during the past two years.  

	None of the respondents from independent investigative sites and community hospitals perceive that their regulatory compliance burden has diminished compared to two years ago. Less than 10% of respondents from clinical research functions within academic medical centers perceive that their regulatory burden has decreased.

	Investigative sites mention a variety of factors that are contributing to increased compliance burden. Top factors include increased regulatory requirements (73% mention) and more complex protocols (66% mention). Increased reporting requirements for adverse events and protocol deviations are mentioned by 53% of investigative sites. 

	Independent investigative sites report that two staff members are typically involved in managing regulatory compliance tasks. Each member manages a mix of clerical, regulatory, and sponsor/CRO related compliance tasks for an average of six studies at any given time. AMCs and community hospitals report that an average of three staff is involved with regulatory compliance tasks. But whereas each dedicated staff member manages tasks for an average of seven studies at community hospitals, within AMCs, each staff member

 manages regulatory compliance tasks for an average of 3.3 studies. Compliance burden per study is likely higher within academic centers, given additional institutional reporting and compliance requirements.

	Half of investigative sites report that study coordinators are typically the primary individuals involved with managing regulatory compliance tasks.  Less than 20% of sites indicate that the principal investigator primarily handles these tasks. Approximately 30% of sites report that a dedicated regulatory specialist is primarily involved with managing compliance tasks.

	In all, respondents provided workload-as measured by hours of time-for 25 regulatory compliance tasks on the survey. Clerical tasks assessed include handling study compliance documentation and correspondences, obtaining signatures, and general communication and reporting. Regulatory tasks include good clinical practice and protocol-specific training and document creation and editing. Sponsor/CRO tasks assessed include preparing for audit and monitoring visits, reviewing material with the study monitor or auditor and post visit follow-up.

	The most time-consuming regulatory compliance tasks are associated with learning sponsor/CRO’s investigator or regulatory web portals and protocol-specific training. Sites report that 20 hours per study is devoted to these specific tasks. Reviewing regulatory documentation with the study monitor or auditor, following up with monitors and auditors after visits, reviewing correspondences and documentation, and filing staff credentials are also cited as the most time-consuming tasks. On a weekly basis, half of a staff member’s time is devoted to preparing for, meeting with, following up with, and reviewing correspondences with study monitors and auditors. 

	Staff involved with managing regulatory compliance tasks appears overloaded. Less than half-46%-of investigative sites report that they are on schedule with their management of regulatory compliance tasks. One-quarter (28%) are approximately one week behind and 26% report being at least two weeks behind on their compliance-related tasks.

	Regulatory compliance requires sites to physically store records and absorb most of the archiving costs, often for 11 years or longer. The predominant storage format across all types of clinical study documentation is a combination of paper and electronic. Of all respondents (i.e., combined independent, AMCs, and community hospitals), eight out of 10 report storing their regulatory and clinical data documents using a combination of paper and electronic formats. An eye-opening 25% of independent investigative sites stores their documents in paper format only.

	Half of respondents indicate that their research center dedicates approximately 20% of their physical office space or more to store paper regulatory documents, including printouts of emails and electronic file attachments.  About half (54%) of respondents report that four or more binders are used to store regulatory documents for a single study  and most said that each document typically exceeded 250 pages in length. A majority of sites indicate that they contract with outside companies to augment their limited in-house storage space. 

	Four out of 10 (44%) respondents exchange ethical review submission documents with their institutional review board (IRB) using electronic formats, compared to about half (48%) that use a combination of paper and electronic formats. The most commonly used method for the exchange of regulatory documents is email, followed by a sponsor/CRO web portal and fax. 

	The majority (79%) of investigative sites report that sponsors are not sufficiently compensating sites for all of their regulatory compliance expenses. The results of this study support this claim.

	Respondents were asked to estimate total site-operating costs-staff time plus infrastructure required-to cover regulatory compliance tasks associated with a single study. The median estimate came to $6,550. Based on itemized costs (including paper, folders, binders, storage boxes, document storage, and regulatory software) and specific staff hours per regulatory compliance task per study, the total average aggregate cost is $13,901, more than double the median per study estimate from sites.

	Sites are reimbursed a median $3,000 per study, about 80% of the median estimated regulatory start-up cost of $3,750 but less than 50% of the estimated regulatory compliance cost and only one-quarter of the actual per-study cost burden. Given the average number of active studies conducted annually, overall site operating profits would nearly triple if sites were remunerated 80% of their total actual study-specific regulatory compliance cost.

	Investigative site regulatory compliance is mission critical. Still, the results of this new study suggest that this burden may be requiring an inordinate amount of staff capacity and infrastructure that is significantly diminishing site operating profit, and may be harming operating efficiency and performance.

	For less established and less sophisticated investigative sites, the burden of regulatory compliance may be hurting their long-term viability. Indeed, nearly 60% of novice investigators drop out of the clinical research enterprise, choosing not to conduct another FDA-regulated clinical trial. The No. 1 reason given: the heavy burden of regulatory compliance.

	The results of this study help quantify how sites are managing regulatory compliance. The results suggest opportunities for electronic technology solutions to help streamline regulatory document storage and exchange capabilities and to reduce infrastructure requirements. The results also suggest the need for regulatory professionals, sponsors, and CROs to scrutinize regulatory compliance tasks and identify ways to simplify the compliance burden. Focusing attention and implementing steps to ease the regulatory compliance burden may go far in helping to improve site performance and sponsor-site and CRO-site relationship quality.

, MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, e-mail: 

CTI Insights

Study takes rare look at the financial and resource burden for sites in managing regulatory compliance.

Characterizing the Real Cost of Site Regulatory Compliance

The patent cliff that rocked big pharma is now starting to reverberate in companies developing generic alternatives. As the slate of top-selling pharmaceuticals going off-patent declines, competition is heating up in generics to find new ways to remain profitable after the financial hits they expect to take starting as early as 2016.

	Generic drugmakers are responding to the situation in a variety of ways. Some generic companies such as Watson, which acquired European competitor Actavis in October 2012, are counting on economies of scale to remain profitable, while others are redefining themselves by specializing in hard-to-make products or by seeking to make their own branded products.

	Manufacturers may seek approval for their products through three possible types of applications under section 505 of the Federal Food, Drug and Cosmetic Act. Section 505(b)(1) is the traditional route of approval, which can require years of clinical trials and millions of dollars in development cost, but offers owners years of market exclusivity in which to recoup their investment. Once a product has gone “off-patent,” application can be made under 505(j) to produce an exact copy or generic version of the drug, but in this case, market exclusivity is only available to the first company to file, and then only for 180 days.

	A third way to seek FDA approval is through the 505(b)(2) application process, which allows companies to file new drug applications (NDAs) utilizing some pivotal data already existing in the public domain. Using this pathway as outlined in the official “FDA Guidance for Industry: Applications Covered by Section 505(b)(2),” drugs can be developed and achieve FDA approval in as little as 30 months, with only a fraction of the number of required clinical trials and with a return on investment higher than many generic drugs.

	Additionally, unlike generic drug applicants, the 505(b)(2) applicant may qualify for three, five, or even seven years of market exclusivity depending on the extent of the change to the previously approved drug and the type of clinical data included in the NDA.

	Given these advantages, it’s no wonder that generic companies might find 505(b)(2) appealing. But 505(b)(2) isn’t just another regulatory pathway, it’s a whole different process that requires its own understanding.

	Prior to 1984, the FDA had an informal policy to review and approve NDAs based solely on literature. These “paper NDAs” were also used for exact copies of approved drugs-generics-which, at the time, lacked formal approval requirements.

	Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act was established by the Hatch-Waxman Amendments of 1984 to allow

 sponsors to obtain approval of NDAs containin  investigations of safety and effectiveness that were not conducted by or for the applicant, but for which the FDA has issued an approval. The section was added to avoid unnecessary duplication of studies already performed on the reference drug.

	However, sponsors must still provide any additional data necessary to ensure that the differences from the reference drug and other existing information do not compromise safety and effectiveness. Today, 505(b)(2) can provide relatively fast-track approval for a wide range of products, especially for those that represent a limited change from a previously approved drug. Thus, an essential difference between an NDA filed for an innovator drug under 505(b)(1) and the NDA filed under 505(b)(2) is the reliance by the sponsors on the use of public information in lieu of conducting the studies themselves.

	Because of the way they typically bring products to market, generic companies may lack the scientific staff required for sourcing the scientific literature, evaluating its utility, and presenting it to the FDA, and they often need to utilize external resources. However, whether an NDA is filed under 505(b)(1) or 505(b)(2), the FDA standards for the demonstration of efficacy and safety are the same. This underscores the necessity of a sponsor to be able to determine what constitutes sufficient evidence and to determine which specific studies can be replaced by existing information in order to gain approval of the investigational drug product under 505(b)(2).

	When published data provides a way to apply the known effectiveness of a drug to a new population or to a different dose, regimen or dosage form, the effectiveness of a new product may be adequately demonstrated without any additional clinical efficacy trials. These situations include:

 The FDA must conclude that the course of the disease and the effects of the drug are sufficiently similar to permit extrapolation from adult efficacy data to pediatric patients. Evidence may include common pathophysiology of the disease, common drug metabolism, and/or experience with other drugs in its therapeutic class.

 Alternative formulations and new dosage strengths may be assessed on the basis of evidence of bioequivalence.

 In some cases, modified-release dosage forms may be approved on the basis of pharmacokinetic data linking the new dosage form to an approved immediate-release dosage form.

Different doses, regimens, or dosage forms.

 Where blood levels and exposure are not very different, it may be possible to conclude that a new dose, regimen, or dosage form is effective on the basis of pharmacokinetic data alone.

	In addition, a single clinical study of a new use, when combined with independent substantiation from published study data in related uses, can often provide adequate evidence of effectiveness in, for example, different doses, regimens or dosage forms; in other phases of the disease or closely related diseases; or in other populations.

	The approval of FOSAMAX PLUS D illustrates the use of existing publicly available data. FOSAMAX demonstrated reduced risk of both hip and spine fractures in postmenopausal women with osteoporosis. In the clinical trials used for the original approval, Vitamin D was a required supplement. In 2005, the FDA approved a new product, FOSAMAX PLUS D, which added the benefit of a weekly dose of Vitamin D. Using 505(b)(2), only published data supporting the independent efficacy of Vitamin D and a single pharmacokinetic study were required.

	Significant value can result from the 505(b)(2) pathway. The following examples demonstrate the potential return on investment (ROI) from a strategic 505(b)(2) development program.

	Although Pentamidine had been approved for sleeping sickness, research uncovered a new indication as a treatment and prophylaxis for AIDS-related Pneumocystis pneumonia (PCP)-an orphan indication eligible for seven years of market exclusivity. In addition, Pentamidine was reformulated through the 505(b)(2) into an aerosolized dosage form that reduced side effects. The company was sold for more than $1 billion.

	Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections. Administered orally or intravenously, it is well known for its severe and potentially lethal side effects, including high fever, shaking, chills, hypotension, vomiting, headache, dyspnea, and tachypnea. Reformulated as a liposome through 505(b)(2), the new product discourages generic competition because it is difficult to copy and manufacture, yet it dramatically reduces side effects and improves efficacy. More than $300 million in sales have been made with only a small hospital-based sales force.

	Originally approved for reducing gastric and other secretions intravenously before surgery as well as for use during anesthesia and intubation, a glycopyrrolate tablet formulation was approved for peptic ulcers. Research into new indications and formulations led to the development under 505(b)(2) of a liquid formulation for cerebral palsy patients to reduce drooling. The new drug was granted orphan-drug status for new indications. It is also currently being developed as a long-acting muscarinic antagonist (LAMA) for COPD patients in multiple-dose inhaler, dry powder inhaler and nebulized dosage forms. The estimated market potential for these new indications exceeds $1 billion.

	The key factor behind these successes is the strategic planning that occurred first. Because generic companies have historically produced only copies of other products, they often lack the background to evaluate the scientific, medical, regulatory, and commercial feasibility of proposed differentiated drug products-and all are vital to market success and ROI.

	The 505(b)(2) process is ideal for reformulations of existing products that address different indications, populations, or routes of administration. However, being able to technically prepare a new formula based on an existing drug is not enough on which to base a go/no-go decision to pursue a 505(b)(2) development program. Before deciding on a product to pursue, sponsors should know details of key factors influencing the pharmaceutical marketplace and regulatory status, as well as the nonclinical and clinical strategy that would be involved in the development of a specific drug, in order to avoid potentially destructive financial risks.

	There are two distinct approaches companies are taking to identify candidates for possible development. Larger pharmaceutical and biotech companies often have a proprietary list of candidates and seek assistance in evaluating which candidates hold the greatest promise. Instead of a list of products, other companies are seeking assistance to identify viable products using selection criteria unique to their business.

	In either situation, it is important to evaluate candidates against four interrelated criteria to determine if they can be successfully developed under 505(b)(2). It’s a process similar to Camargo Pharmaceutical Services’ proprietary Ready 4 Action process. This four-step process addresses:

 Does the science make sense? For instance, is the formulation or chemistry practically and pragmatically achievable? Is it scalable? Are API ingredients available and affordable?

 Does the product have a clear niche in the medical specialty? Is it effective for solving a unique problem or solving a problem in a unique way? Does it present acceptable risk/benefit? Is it appealing to the proposed patient population?

 What clinical trials or other data will be required to gain approval? Can development be expedited? What distinguishing information can be presented on the labeling for eventual promotional activity?

 Is there a viable market for the product? What is the potential for future competition or substitution? What is needed to ensure reimbursement? What is the optimal pricing?

	Evaluating candidates on all four of these criteria is critical. For example, assessing whether a product can be effectively marketed at a profit and verifying market requirements before development begins helps inform the design of studies to meet various objectives, such as gaining essential labeling language.

	One essential tool now being used in the development and strategic management of new or modified drugs/biologics/devices is the Target Product Profile (TPP). Basically, it is a summary of the proposed drug development program described in terms of the labeling concepts. Its purpose is to focus discussions and aid in the understanding between sponsors and the FDA.

	As the FDA itself says in its guidance, “The TPP embodies the notion of beginning with the goal in mind.”

 Utilizing this methodology, the sponsor must envision the end product, including the target population, the formulation, the dosage form and strength, etc., as a means of expressing the goals of the product along with the specific studies needed to support the labeling concepts.

	By evaluating candidates on these four criteria, sponsors can identify candidates with sound scientific footing to meet the requirements of a 505(b)(2), and those that also have enough differentiation to be commercially viable. A comprehensive drug development plan must be provided that includes testing, formulation, and manufacturing, along with a plan for conducting any needed preclinical and clinical studies. With this plan in hand, it is advisable to gain FDA’s concurrence, usually by requesting a pre-investigational new drug (IND) meeting. 

	Furthermore, before choosing a product to develop, it’s important to have an assessment of the sponsor’s assets, specific goals, and business needs. The criteria that are germane to this are many and may include everything from existing products or APIs the client holds, to market areas it wishes to enter or targeted populations/therapeutic segments it wishes to address.

	Identifying viable candidates is essential, but deciding whether a company should pursue development is also critical. There are four steps to deciding what product to pursue: criteria selection, criteria evaluation, candidate narrowing, and candidate selection. Although every company will utilize a unique set of criteria, a typical chart and range of values may look something like what is illustrated in Table 1.

	Once the criteria are established, potential products are evaluated against the criteria as part of the second step. In the third step, candidate narrowing, the object is to refine the list by choosing the most important criteria and investigating in sufficient detail to clearly identify the most attractive options. If, for example, conducting Phase III trials in order to gain market exclusivity is a key goal of the sponsor, candidates that didn’t meet that criterion would be deleted from the list.

	This narrowing of focus is essential to get beyond broad and unmanageable marketing segments, such as indications or diseases, in order to pinpoint highly specific definitions of unique products and discrete market segments. The research effort required will span the scientific, medical, regulatory, and commercial space because all these elements must work in tandem to create a product that can be defined, differentiated from what else is available, and effectively marketed at a profit.

	In the final stage, candidate selection, detailed research is undertaken. Consideration should be given to a broad range of research concerning the market, the product, manufacturing, and regulatory affairs, as well as marketing and investor strategy.

	To gain the depth of understanding required, research may begin with a detailed overview of the disease or condition under consideration, including analyses of the current standards of care and a market-needs assessment. This, along with a strengths-weaknesses-opportunities-threats (SWOT) analysis of the product’s potential to strategically address market needs, helps develop product positioning and the target product profile.

	Additionally, sponsors must evaluate the regulatory issues that must be addressed and establish the physicochemical properties of the product, including its chemical makeup, stability, and solubility, as well as the specific route of administration. Determining whether the product may be made available as a capsule, tablet, aerosol, liquid, or as a subcutaneous, intramuscular, or intravenous injection will also have a bearing on the suitability of a 505(b)(2) approach to approval.

	Finally, because maximizing ROI is the ultimate goal, it’s important to have a firm grasp on the market you’ll be entering, including the competitive landscape and the issues that may impact your distribution plan. Having developed answers to these questions in addition to having a pricing and payer reimbursement plan in place will put you in a much stronger position to identify potential partners and negotiate with investors.

	With this research, a company can ascertain the viability of a product and also whether the product is a good fit for their particular business. And, with these results in hand, companies can begin to devise a comprehensive development plan with confidence.

	The traditional dynamics of the generic market allow for all the competing generic manufacturers to calculate the potential value of the total market for a drug once it loses patent protection. What they don’t know is how many rivals are likely to enter the same market and what impact that number of competitors will have on their profits.

	A study of generic drug industry dynamics showed that generic drug prices fall with a significant increase in the number of competitors, but remain above long-run marginal cost until there are eight or more.

 However, because a generic version of an off-patent drug still requires FDA approval, firms must make a significant application investment before knowing when or how much competition they will face, or when or if they will make a profit.

	The same cannot be said for the differentiated products developed under 505(b)(2). By partnering with companies that specialize in 505(b)(2) development, generic companies can acquire the specialized expertise they need to gain market approval. However, to determine true product viability, generic companies should seek help from companies not just experienced in the 505(b)(2) pathway, but from companies that can also demonstrate expertise in a variety of areas, including clinical development, intellectual property, and product revenue forecasting.

	To effectively develop products under 505(b)(2), it’s vital to have a robust relationship with the FDA, as well as a firm understanding of the types and sufficiency of product patents that are acceptable with this strategy. Generic companies can also benefit from specialized knowledge in developing sales and marketing strategies, as well as cogent advice on compendia positioning, pricing, distribution, product liability, and risk management.

	Given the cost of drug development today, the time and money involved in planning represent a prudent investment to move forward with development of a successfully marketable product.

	In the future, pharmaceutical and biotech companies of all sizes are going to have to adjust their strategies to remain competitive. Some big pharma companies still have their sights set on blockbusters coming from biologics. For example, Johnson & Johnson’s and Pharmacyclics’ ibrutinib was approved by the FDA as Imbruvica in November 2013 for the treatment of mantle cell lymphoma and in February 2014 for the treatment of chronic lymphocytic leukemia. Ibrutinib had been designated a breakthrough therapy by the FDA, granting it an accelerated approval process, and is one of the most promising late-stage cancer treatments on the market, with a potential to earn $1.3 billion a year.

	But these biologic drugs cost several-fold more to develop than small molecules, and are out of reach financially for most generics companies. The patent cliff will shrink the opportunities for making generics and cause big pharma to consider means of extending the value of existing products. Thus, both generics and big pharma companies will need to find additional sources of revenue. The 505(b)(2) pathway can provide a useful mechanism for the industry to replace or augment revenues.

	Research-based companies with products facing patent expiration may ï¬nd that the 505(b)(2) pathway can provide a useful mechanism to extend market exclusivity. For generics companies, the 505(b)(2) pathway can be a powerful tool to improve the revenue stream by identifying niche branded products and marching in a different direction than competitors.

	As previously stated, products approved through the 505(b)(2) pathway may qualify for three, five, or even seven years of market exclusivity, depending on the extent of the change to the previously approved drug and the type of clinical data included in the NDA. 505(b)(2) success hinges on identifying products that have documented market differentiation, low development risk, and high proï¬t potential. Moreover, the 505(b)(2) pathway comes with unique and demanding requirements that are difficult to navigate. Sponsors beneï¬t from employing a deliberative, step-by-step approach led by a team of experts with the commercialization, drug development, and regulatory expertise to synthesize a viable 505(b)(2) development plan.

	From 2010 to 2013, 43% of all NDAs approved have been 505(b)(2) drugs.

 In 2014, this number was 50%, with 41 new 505(b)(2) drugs approved compared to the same number of new molecular entities (NMEs).

 This percentage is expected to rise to more than 80% over the next few years.

 In the ï¬nal analysis, 505(b)(2) development is more than just a regulatory pathway, it is a unique strategy that can often result in product approval with lower risk, reduced development cost, and faster speed to market.

 is President and CEO, Camargo Pharmaceutical Services.

	1. Thomas K, “Generic Drug Makers See a Drought Ahead,” 

http://www.nytimes.com/2012/12/04/business/generic-drug-makers-facing-squeeze-on-revenue.html

	 2. Center for Drug Evaluation and Research, Food and Drug Administration, 2005, 

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021762s000_Fosamax_Plus_D_MEDR.pdf

	3. “Guidance for Industry and Review Staff: Target Product Profile,” Food and Drug Administration, March 2007, 

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm080593.pdf 

	4. Reiffen D and Ward MN., “Generic Drug Industry Dynamics,” Federal Trade Commission, 2002

	5. Cundari A, 505(b)(2) approvals 2010 to 2013, Akesis, 2013, available at: 

http://akesis.com/blog/2013/12/505b2-approvals-2010-2013-2/

	6.  FDA Center for Drug Evaluation and Research (CDER), Novel New Drugs–2014 Summary, available at: 

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM430299.pdf

	7. Orans J, 2014 505(b)(2) NDA Approvals, Camargo Pharmaceuticals Blog, available at: 

http://blog.camargopharma.com/index.php/2015/01/17/2014-505b2-nda-approvals/

	8. Phelps K, “(B)(2) or not (B)(2) – That is the Question.” 505(b)(2) can result in product approval with lower risk, reduced costs, and faster time to market, Contract Pharma, Nov. 6, 2013, available at: 

http://www.contractpharma.com/contents/view_experts-opinion/2013-11-06/b2-or-not-b2---that-is-the-question/

is President and CEO, Camargo Pharmaceutical Services

Feature Article

Understanding the benefits of this application route in helping companies withstand the hit of patent expiries.

Using 505(b)(2) to Solve Shortfall from Generic Cliff

Computer-based modeling and simulation has advanced numerous industries, from aeronautics and engineering to meteorology and finance. Its potential benefits in drug discovery and development have been recognized for decades, but full realization of modeling and simulation in the health sciences has been limited by the vast complexity of biological systems, lack of understanding of disease, lack of large-population data on real-world health outcomes, and uncertainty regarding regulatory acceptance of modeling and simulation applications in clinical drug evaluation. These barriers are gradually being overcome, and modeling and simulation is now poised to transform the entire drug development lifecycle, from discovery to commercialization.

		Modeling and simulation (M&S) practice has evolved to solve complex problems that could not be addressed using direct observation and measurement. Models are built using historical observations to describe behaviors observed within systems. Models are commonly used to predict a future outcome and can be either deterministic or probabilistic (stochastic). Simulations use models to test how variability within a system can impact outcomes. Simulations can use more extreme model inputs than have been observed to help characterize the range of potential outcomes. In this way, simulation can be used to better understand risk and identify opportunities to improve outcomes. 

		In clinical drug development, M&S is used to quantified problems and test assumptions as a means to improve decision-making and increase predictability. Emerging applications are now being used to predict drug safety and efficacy, to plan individual trials and Phase I to III development programs, and to better manage research portfolios.

 These applications offer a glimpse of the biopharmaceutical industry’s modeling and simulation-informed future-more focused communication among development experts, greater efficiencies, and higher success rates. M&S will foster a knowledge-based drug development process that creates more value for patients, payers, and healthcare providers.

Benefits: More predictability, better decisions 

		Predictability is the fundamental challenge of drug development. In the Food and Drug Administration’s (FDA) 2004 report on Critical Path needs and opportunities, regulators called for an aggressive, collaborative effort to create a new generation of predictive tools that could reduce costly development failures: “As biomedical knowledge increases and bioinformatics capability likewise grows, there is hope that greater predictive power may be obtained from in silico (computer modeling) analyses.”

		Computer-based predictive models are essential tools to increase clinical trial efficiencies and probability of success in what FDA envisions as “model-based drug development.” In model-based development, pharmaco-statistical models of drug efficacy and safety are built from available preclinical and clinical data with expert opinion to determine M&S objectives and inputs for simulation. Models are used to simulate scenarios of predicted relationships between drug exposure, drug response, and patient outcomes. 

		M&S informs decision-making by leveraging early data to guide downstream decisions and strategies. When practiced across the full development lifecycle, M&S drives more efficient ways of working based on wider applications of data and on communication across disciplines and operations. It places greater reliance on evidence rather than on assumptions; where assumptions are necessary, M&S predicts their implications across a range of assumptions.

		To implement well-informed modeling and simulation, it is necessary to eliminate traditional research silos that inhibit information sharing. M&S practice encourages closer collaboration among development experts from

 different disciplines. Their combined knowledge ensures that M&S assumptions are reasonable and results are interpreted correctly. By fostering collaboration, M&S adds value by leveraging knowledge across the full drug innovation lifecycle.

The most mature practice and best current example of the value of M&S in drug development is pharmacokinetic/pharmacodynamic (PK/PD) dose modeling.

 This M&S application, which is heavily dependent on cross-functional collaboration, has dramatically improved dose determination-increasing predictability and reducing time and cost by leveraging data as it accrues, from preclinical to Phase III studies.

		By clarifying a drug’s exposure-response relationship, PK/PD models can be used to predict optimal dosing regimens for patient testing, to provide insight on endpoints, and to test a range of assumptions about clinical outcomes. Population PK/PD analyses help identify dose adjustments for special populations such as children, the elderly, ethnic groups, patients with impaired renal/hepatic function, and patients likely to experience drug-drug interactions. They do so by better understanding patterns in the exposure-response relationship and their variability.

Enabling knowledge-based decisions: Trial design simulations. 

M&S facilitates knowledge-based decision-making by quantifying problems and providing a basis for discussion and assessment in a multifunctional team, particularly when there is uncertainty about the safety or efficacy profile of a therapy. For example, one of the authors modeled a number of different strategies that might be used to gain regulatory approval for a treatment indication pertaining to the central nervous system. Each strategy included interdependent Phase IIa, IIb, and Phase III studies. Success or failure at each stage was simulated for a range of plausible assumptions about safety and efficacy, based on evidence from preclinical and early clinical results. The simulated “what if” scenarios helped experts to evaluate each possible strategy. These simulations gave rise to fruitful interdisciplinary discussions about the assumptions that should be used, both pessimistic and optimistic. In addition, they provided an easily shared basis for clinicians, statisticians, regulatory affairs experts, and health economists to work together to make informed, knowledge-based choices for the development plan. Here, the value of M&S was in fostering informed discussion about the risks and benefits of each strategy among diverse experts, rather than in identifying the “best” design.

Managing complexity: Predicting market performance.

 Modeling and simulation can improve commercial decision-making by taking into account more of the complex variables inherent in the post-marketing landscape. Effective management of a biopharma company’s development portfolio requires assessment of therapeutic benefit, safety, commercial competitiveness, and cost-effectiveness-assessments that change as each drug candidate advances through development. Unpredictable development timelines and costs, regulatory changes, and evolving market conditions pose additional uncertainties. M&S can provide more reliable predictions of a product’s market potential by addressing complex commercial questions. For example, compared to existing products, how much better do therapeutic outcomes have to be for a drug to gain formulary acceptance?

		Creating a statistical model of a portfolio allows developers to simulate various changes to the portfolio and their resulting impact on the likelihood that the portfolio will support business objectives. Simulations can be used to evaluate

 portfolio tradeoffs through the probabilistic representation of key performance metrics, such as time in development phase and development costs. M&S applications in portfolio management are now being used to understand the impact of tradeoffs (i.e., whether or not to add a risky development project to an existing portfolio) in the context of total portfolio risk and return. “What if” scenarios can help developers consider the probability that a company will meet a specific revenue threshold in a given year, or launch a target number of new products in a given timeframe. Figure 1 shows an analysis of varying development timelines on commercial impact.

			Regulatory endorsement is a major driver of the expanding use of pharmacometric (quantitative pharmacology) models to simulate relationships between drug exposure, drug response, and individual patient characteristics. FDA’s 2009 

Guidance for Industry: End-of-Phase 2A Meetings

 encourages sponsors to seek regulatory meetings to discuss quantitative modeling and trial simulations to improve dose selection.

 In cardiovascular safety evaluation, the FDA’s Office of Clinical Pharmacology often recommends concentration-QT (C-QT) modeling as a means of better evaluating drug potential for QT interval disturbance.

A 2011 review conducted by FDA’s three-year-old Division of Pharmacometrics found a dramatic increase in both the number of reviews with pharmacometric analyses and their impact on FDA’s drug approval and labeling decisions.

 For 198 applications submitted between 2000 and 2008, pharmacometric analyses contributed to approval decisions in 126 applications. In 50% of these applications, M&S provided either pivotal or supportive insights into effectiveness; in 43%, M&S provided pivotal or supportive insights into safety. Pharmacometric analyses impacted labeling decisions in 133 applications. In 41% of those, M&S informed dosage and administration labeling, and in 14%, M&S contributed to safety labeling.

			The review points to additional uses of pharmacometric models. FDA is using M&S to select pediatric dosing regimens and to approve drug dosages not studied in Phase III trials. There is also “an increasing trend toward use of model-based primary endpoints in pivotal trials, such as slope in a dose (exposure)-response model.”

 The report notes that five of the 198 new drug application (NDA) submissions just discussed used such model-based endpoints. Two of these submissions were indicated for pediatric epilepsy, and the primary endpoints used were slopes of the dose-response relationship and exposure-response relationship in the reduction of seizure frequency.

			Another notable trend is toward the application of M&S as a pathway to regulatory acceptance of a single Phase III trial, plus a causal evidence model for demonstration of drug safety and efficacy. A provision of FDA's Modernization Act of 1997 (section 115a) allows new drug approval based on data from one adequate and well-controlled investigation, plus confirmatory evidence.

 This model has received increasing attention as a more rational, efficient, and informative approach to clinical development.

There are a number of barriers to the broader application of lifecycle M&S. Despite the compelling value of M&S in clinical research and regulatory review, newer M&S applications still pose uncertainties and industry has been slow to adopt applications that go beyond PK/PD modeling. Organizations tend to accept widely understood approaches, and M&S is still unfamiliar in many applications. Thorough and careful pre-specification is often required by regulators, especially for game-changing uses of M&S in new drug applications. 

			M&S also requires special expertise and new ways of working. There are economic barriers as well. M&S takes time to develop and adds cost to lean research budgets.

The bottom line for industry is: Will an investment in M&S pay off in terms of greater predictability? The following discussion provides examples of emerging M&S development applications and their benefits.

			There is growing acceptance of M&S to inform clinical trial design. Simulated trials are used to “test-run” various designs; results predict likely outcomes for a range of assumptions pertaining to dose, trial size, and operational considerations.

Virtual patients can be created at the individual level using health records, PK/PD data, and historic data. Patient attributes also can be added to virtual patients to describe behaviors, such as adherence to treatment and other study procedures. These virtual patients can then be enrolled based on inclusion/exclusion criteria for clinical trial simulations.

Example: Informing enrollment criteria. 

Archimedes Inc. recently conducted a simulated trial to help researchers define inclusion/exclusion criteria and gain information for powering a diabetes study.

How the application of evolving M&S models are transforming full-research design strategies.

Applied Clinical Trials-06-01-2015

FDA Seeks Resources to Support New Research Initiatives

Safety Considerations for Follow-On Non-Biologic Complex Drugs

Putting the EMA House in Order

Experts Call for Urgent Action on Antibiotics Research

Oncology Leads Personalized Medicine

Characterizing the Real Cost of Site Regulatory Compliance

Using 505(b)(2) to Solve Shortfall from Generic Cliff

Lifecycle Modeling and Simulation in Clinical Trials

The U.S. Biosimilar Pathway: Policy Precedes Science

Managing Portfolios for Economic and Clinical Value

Applied Clinical Trials Digital Edition - June/July 2015