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Posts Tagged ‘Clinical Trials’

Paclitaxel: Pharmacokinetic (PK), Pharmacodynamic (PD) and Pharmacogenpmics (PG)

Posted in BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged , , , , , , , , , , , , , , on November 27, 2012| 5 Comments »

Author: Tilda Barliya PhD

In response to the previous post:

Paclitaxel vs Abraxane (albumin-bound paclitaxel)

http://pharmaceuticalintelligence.com/2012/11/17/paclitaxel-vs-abraxane-albumin-bound-paclitaxel/

Pharmacogenomics properties are presented, below.

Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute (North Carolina)  in 1967 when Monroe E.Wall and Mansukh C.Wani  isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol. Later it was discovered that endophytic fungi in the bark synthesize paclitaxel.

Paclitaxel is currently being indicated to lung, breast and ovarian cancer as well as  head and neck cancer, and advanced forms of Kaposi’s sarcoma. 

The administration of paclitaxel (Taxol®) through intravenous infusions was achieved by using Cremophor® EL as a vehicle to entrap the drug in micelles and keep it in solution, which affects the disposition of paclitaxel and is responsible for the nonlinear pharmacokinetics of the drug, especially at higher dose levels. (http://www.futuremedicine.com/doi/pdf/10.2217/pgs.10.32)

Although Nonlinear pharmacokinetics (dose-dependented kinetics) may occur in all aspects of pharmacokinetics (absorption, distribution, and/or elimination), it focus on the in the metabolism or MichaelisMenten (MM) kinetics of the drug. http://archive.ajpe.org/legacy/pdfs/aj650212.pdf

Briefly, it is known that some of these adverse effects such as hypersensitivity reactions were diminished with the administration of corticosteroids and H1 and H2 antihistamine premedication, and by reducing the incidence of grade 3/4 neutropenia with the administration of granulocyte colony-stimulating factors (G-CSF) and shortening paclitaxel infusion time from 24 to 3 h. However, the neurotoxicity, which was believed to be caused by either paclitaxel or Cremophor EL, could not be controlled and became the dose-limiting toxicity of the drug. It was later on found that paclitaxel itself was responsible to the neurotoxicity effects (http://annonc.oxfordjournals.org/content/6/7/699.abstract)

Pharmacokinetics and Pharmacodynamics

The selection of pharmacokinetic (PK) parameter end points and basic model types for exposure-toxicity relationships of paclitaxel is usually based on tradition rather than physiological relevance.

pharmacokinetic (PK)-pharmacodynamic (PD) relationships for paclitaxel are still most commonly described with empirically-designed threshold models, which have little or no mechanistic basis and lack usefulness when applied to conditions (eg, schedules, vehicles, or routes of administration) different from those from which they were originally derived. (http://jco.ascopubs.org/content/21/14/2803.long). As such, the AUC of the unbound paclitaxel is highly important as a pharmacokinetic parameter to describe exposure-neutropenia relationships (the unbound ptx was not evaluated yet). (http://clincancerres.aacrjournals.org.rproxy.tau.ac.il/content/1/6/599.full.pdf+html)

The clearance of Cremophor EL in patients was found to be time-dependent, resulting in disproportional increases in systemic exposure being associated with shortening of infusion from 3 hours to 1 hour.

One study (http://clincancerres.aacrjournals.org/content/1/6/599), compare the pharmacokinetics and pharmacodynamics (PD) of paclitaxel between Phase I trials of 3- and 24-h infusions and to determine the most informative pharmacokinetic parameter to describe the PD. The study had 3 main goals

  • (a) to compare the PK and PD of paclitaxel between Phase I studies of 3- and 24-h infusion,
  • (b) to examine the relationship between PK and PD
  • (c) to determine the most informative pharmacokinetic parameter to describe the PD.

Note: Although this study was conducted in ~1993-1995, is has been cited extensively and paved the was to other clinical trials with similar results.

27 patients were treated in a Phase I study of paclitaxel by a 3-h infusion at one of six doses: 105, 135, 180, 210, 240, and 270 mg/m2. Pharmacokinetic data were obtained from all patients. Paclitaxel concentrations were measured in the plasma and urine using HPLC. Similar eligibility criteria were designed for the 24-hr infusion with these doses were 49.5, 75, 105, 135, and 180 mg/m2 . Plasma and urine samples for pharmacokinetic evaluation of paclitaxel were collected.

Pharmacokinetic Analysis: Pharmacokinetic parameters, Cmax, AUC, t112, and MRT were obtained by a noncompartmental moment method. Cmax was actually observed peak concentration. AUC and MRT were computed by trapezoidal integration with extrapolation to infinite time.

Pharmacodynamic Analysis: The pharmacokinetic/pharmacodynamic relationships were modeled with the sigmoid maximum effect

Results:

Pharmacokinetic analysis:

The drug plasma concentration increased throughout the 3-h infusion period and began to decrease immediately upon cessation of the infusion with t112 of 9.9-16.0 h and MRT of 6.47-10.24 h (Fig. 1). Both Cmax and AUC increased with increasing doses (r = 0.865, P <0.001 for Cmax r 0.870, P < 0.001 for AUC), although the pharmacokinetic behavior appeared to be nonlinear (Fig. 2). The mean Cmax and AUC at a dose of 270 mg/m2 were more than 3-fold greater than those at a dose of 135 mg/m2. CL and V, decreased with increasing doses (Table 1). The urinary excretion of paclitaxel over 75 h was less than 15% of the dose administered, which indicated that non-renal excretion is the primary route of drug elimination.

The urinary excretion of paclitaxel over 75 h was less than 15% of the dose administered, which indicated that non-renal excretion is the primary route of drug elimination.

Comparison of PD between 3-h and 24-h Infusion

Groups. AUC and duration of plasma concentration (h) above (7>) 0.05-0.1 LM correlated with the % D in granulocytes with p values less than 0.05. The best parameter predicting granulocytopenia was T> 0.09 pM with the minimum of the Akaike Information Criterion. In the 24-h schedule, dose, AUC, and T > 0.04-0.07 pM were demonstrated to correlate with the % D in granulocytes. The best parameter predicting granulocytopenia in the 24-h schedule was T > 0.05 p.M.

Nonhematological toxicities such as peripheral neuropathy, hypotension, and arthralgialmyalgia mainly observed in the 3-h infusion group had no relationship with Cm or AUC which are much higher in the 3-h infusion group, although peripheral neuropathy and musculoskeletal toxicity have been suggested to be associated with AUC on a 6- (12) or 24-h (29) schedule.

Pharmacogenomics:

In the past, the major adverse effects encountered with Taxol were severe hypersensitivity reactions, mainly attributed to Cremophor EL; hematologic toxicity, primarily appearing in the form of severe neutropenia; and neurotoxicity, mainly seen as cumulative sensory peripheral neuropathy. The mechanism for the neurotoxicity has been demonstrated to involve ganglioneuropathy and axonopathy caused by dysfunctional microtubules in dorsal root ganglia, axons and Schwann cells.

Variability in paclitaxel pharmacokinetics has  been associated with the adverse effects of the  drug. Thus, polymorphisms in genes encoding  paclitaxel-metabolizing enzymes, transporters and therapeutic targets have been suggested  to contribute to the interindividual variability in toxicity and response.

Further characterization of  genes involved in paclitaxel elimination and drug  response was performed, including the identification of their most relevant genetic variants. The organic anion transporting polypeptide (OATP)  1B3 was identified as a key protein for paclitaxel hepatic uptake and polymorphisms in the genes encoding for paclitaxel metabolizing enzymes and transporters (CYP2C8, CYP3A4) CYP3A5, P-glycoprotein and OATP1B3) (http://www.futuremedicine.com/doi/pdf/10.2217/pgs.10.32)

***It is important to note that  the allele frequencies for many of these polymorphisms are subject to important ethnicity  specific differences, with some alleles exclusively present in specific populations (e.g., the Caucasian CYP2C8*3).

For the CYP2C8 gene, two alleles common in Caucasians that result in amino acid changes CYP2C8*3 (R139K; K399R) and CYP2C8*4 (I264M), were described. The former has been shown to possess an altered activity, while the latter does not seem to have functional
consequences. In addition, two CYP2C8 haplotypes were recently shown to confer an increased and reduced metabolizing activity, respectively.

CYP3A5 was found to be highly polymorphic owing to CYP3A5*3, CYP3A5*6 and CYP3A5*7 , with the latter two being African-specific polymorphisms.

Pharmacogenetic studies comparing the most relevant polymorphisms in these genes and paclitaxel pharmacokinetics have rendered contradictory results, with some studies finding no associations while others reported an effect for ABCB1, CYP3A4 or CYP2C8 polymorphisms on specific pharmacokinetic parameters.

Again, with respect to paclitaxel neurotoxicity risk, some studies have rendered positive results for ABCB1 , CYP2C8  and CYP3A5  polymorphisms, while others found no significant associations.

Note: These differences might be caused by underpowered studies and by differences in the patients under study.

Changes affecting microtubule  structure and/or composition have been shown to affect paclitaxel efficacy, probably by reducing drug–target affinity. Mainly, resistance to tubulin-binding agents has been associated with an overexpression of b-tubulin isotype III,
which seems to be caused by a deregulation of the microRNA family 200.

However, the clinical utility of these findings remains to be established; furthermore, the identification of biomarkers that could be used to individualize paclitaxel treatment remains a challenge.

In summary,

  1. Pharmacokinetics: Paclitaxel seems to have a non-linear (=dose-dependent) PK parameters.
  2. Pharmcokinetics- Pharmacodynamics: Previous clinical trials did NOT take into account the unbound concentrations of Ptx and therefore in the PK analysis, therefore newly designed clinical trials should take that into consideration. This is very important since the neurotoxicity is attributed to ptx and not its vehicle Cremophor (as shown in the PD analysis)
  3. Difficult to compare between the 3hr and 24hr infusion schedule as most clinical trials did NOT used similar dose-regime making the comparison very hard.
  4. Pharmacogenetics: Different polymorphisms seems to attribute to the been suggested  to contribute to the interindividual variability in toxicity and response.
  5. Prospective pharmacogenetic-guided clinical trials will be required in order to accurately establish the utility of the identified markers/strategies for patients and healthcare systems.

 

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Overview of New Strategy for Treatment of T2DM: SGLT2 Inhibiting Oral Antidiabetic Agents

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, International Global Work in Pharmaceutical, Metabolomics, Pharmaceutical Analytics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged , , , , , , , , , , , , , , on November 22, 2012| 8 Comments »

Overview of New Strategy for Treatment of T2DM: SGLT2 Inhibiting Oral Antidiabetic Agents

 

Author and Curator: Aviral Vatsa, PhD, MBBS

Type 2 diabetes mellitus (T2DM) is a chronic disease, which is affecting widespread populations in epidemic proportions across the globe 1. It is characterised by hyperglycemia, which if not controlled adequately, eventually leads to microvascular and metabolic complications (Fig 1). Traditionally, T2DM management includes alteration in lifestyle, oral hypoglycemic agents and/or insulin. The present pharmacological approaches predominantly target glucose metabolism by compensating for reduction in insulin secretion and/or insulin action. However, these approaches are often limited by inadequate glucose control and the the possibility of severe adverse effects such as hypoglycemia, weight gain, nausea, and sometimes lactic acidosis 2–4 (Fig 1). Hence the search for new drugs with different mechanism of action and with little side affects is key in providing better glycemic control in T2DM patients and hence offering better prognosis with reduced morbidity and mortality.

Figure 1 (credit: aviral vatsa): Short overview of Type 2 diabetes mellitus (T2DM): complications, present therapeutic approaches and their limitations.

Along with pancreas, our kidneys play a vital role in regulating glucose levels in the plasma. Under physiological conditions, kidneys absorb 99% of the plasma glucose filtered through the renal glomeruli tubules. Majority i.e. 80-90% of this renal glucose resorbtion is mediated via the sodium glucose co-transporter 2 (SGLT2) 5,6. SGLT2 is a high-capacity low-affinity transporter that is mainly located in the proximal segment S1 of the proximal convoluted tubule 6. Inhibition of SGLT2 activity can thus induce glucosuria which inturn can lower blood glucose levels without targeting insulin resistance and insulin secretion pathways of glucose modulation (Fig 2).

Figure 2 (credit: aviral vatsa): Schematic overview of regulation of plasma glucose by sodium glucose co-transporter (SGLT).

Thus inhibition of SGLT2 provides a novel way to modulate blood glucose levels and consequently limit long term complications of hyperglycemia 7,8. Moreover, SGLT2 inhibitors will selectively target the renal glucose transportation and spare the counter regulatory hormones involved in glucose metabolism because SGLT2 is almost exclusively located in the kidneys. This novel way of glucose modulation will likely avoid severe side affects, e.g. hypoglycemia and weight gain, that are seen with present antidiabetic pharmacological agents.

Agents currently under development

Table below gives an overview of the SGLT2 inhibotors in development.

(Credit: Chao et al 2010)

 

In summary, increasing urinary glucose excretion represents a new approach to addressing the challenge of hyperglycaemia. SGLT2 inhibitors may have indications both in the prevention and treatment of T2DM, and perhaps T1DM, with a possible application in obesity. Further studies in large numbers of human subjects are necessary to delineate efficacy, safety and how to most effectively use these agents in the treatment of diabetes.

Bibliography

  1. Diabetes Atlas. International Diabetes Federation, (2009) at <www.diabetesatlas.org>
  2. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).
  3. Buse, J. B. et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27, 2628–2635 (2004).
  4. Inzucchi, S. E. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287, 360–372 (2002).
  5. Brown, G. K. Glucose transporters: Structure, function and consequences of deficiency. Journal of Inherited Metabolic Disease 23, 237–246 (2000).
  6. Wright, E. M. Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 280, F10–F18 (2001).
  7. Chao, E. C. & Henry, R. R. SGLT2 inhibition — a novel strategy for diabetes treatment. Nature Reviews Drug Discovery 9, 551–559 (2010).
  8. Ferrannini, E. & Solini, A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nature Reviews Endocrinology 8, 495–502 (2012).

 

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Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Posted in FDA Regulatory Affairs, Health Economics and Outcomes Research, Health Law & Patient Safety, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , on August 23, 2012| 6 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

 

HEALTH LAW, ETHICS, AND HUMAN RIGHTS

Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Michelle M. Mello, J.D., Ph.D., Steven N. Goodman, M.D., M.H.S., Ph.D., and Ruth R. Faden, Ph.D., M.P.H.

August 22, 2012 (10.1056/NEJMhle1207160)

The tumult arising from revelations of serious safety risks associated with widely prescribed drugs, including rosiglitazone (Avandia, GlaxoSmithKline), rofecoxib (Vioxx, Merck), and celecoxib (Celebrex, Pfizer), has led to widespread recognition that improvement is needed in our national system of ensuring drug safety. Notwithstanding federal legislation in 2007 that strengthened the authority of the Food and Drug Administration (FDA) in the postmarketing period,1 critical weaknesses in the national system persist.

Central to these weaknesses are dilemmas surrounding not only the science but also the ethics of drug-safety research,2 many of which came to the fore in the heated public debate about the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial, which compared the cardiovascular outcomes of long-term treatment with rosiglitazone with those of pioglitazone (Actos, Takeda) in patients with type 2 diabetes.3 At the request of the FDA, an Institute of Medicine (IOM) committee, on which we served, was convened to examine the ethics and science of FDA-required postmarketing safety research. In this article, we review the key ethics findings from the committee’s May 1, 2012, report4 and offer some reflections on the challenges ahead.

LESSONS FROM THE TIDE TRIAL

In May 2008, the FDA ordered the manufacturer of rosiglitazone, GlaxoSmithKline, to conduct a trial in response to evidence from meta-analyses that rosiglitazone was associated with a higher risk of myocardial infarction and death from cardiovascular causes than placebo or medications that were not based on nonthiazolidinedione comparators.5,6 Other studies suggested that pioglitazone, an alternative thiazolidinedione, was not associated with such risks.7,8 Before enrollment began, some argued that the evidence of the inferior safety of rosiglitazone was strong enough to make the trial ethically unjustifiable. Two FDA epidemiologists wrote in a 2008 memorandum that a head-to-head trial “would be unethical and exploitative” and that even a robust informed-consent process could not overcome the problem.9 This was not the consensus FDA view, which was that the uncertainty regarding the cardiovascular risks associated with rosiglitazone, as well as those associated with pioglitazone, was sufficient to justify a trial.10

These concerns triggered a February 2010 letter from members of Congress to the FDA demanding a justification for the trial and alleging that the consent form did not provide adequate risk information.11 In response, FDA Commissioner Margaret Hamburg expanded the FDA investigation of the safety of rosiglitazone, obtained advice from an FDA advisory committee, and asked the IOM to convene our committee.6 Although the FDA advisory committee recommended that the TIDE trial be continued if rosiglitazone was permitted to remain on the market, in September 2010, the FDA halted the trial and placed stringent new restrictions on the availability of rosiglitazone.12,13

The TIDE experience made the FDA appreciate the need for greater attention to the ethics of postmarketing research. First, it posed questions about what standard of evidence about drug risk justifies a decision by the FDA to require postmarketing research, particularly randomized trials, as well as what evidence could render such trials unacceptable. Second, it raised questions about what ethical obligations the FDA has to patients who participate in these studies. Finally, it highlighted a potential FDA role in ensuring that institutional review boards (IRBs) are completely informed in their efforts to protect study participants. Although major deficiencies with the TIDE consent form were identified by some FDA scientists and, later, by the IOM committee (Table 1TABLE 1Major Deficiencies in the Informed-Consent Form for the TIDE Trial.),4,9 the TIDE investigators countered that it had been approved by “480 ethics committees and IRBs.”14 However, the language of the consent form, the trial design, and the materials supporting the justification of the trial raised a question for the IOM committee about whether these bodies adequately understood the nature of the evidence that gave rise to the trial. The IOM committee proposed a framework for evaluating the ethics of FDA-required postmarketing research15 and made a number of ethics findings and recommendations.4

Ethical Responsibilities of the FDA

The IOM committee began by noting that the public health mission of the FDA gives rise to potentially competing ethical obligations “to protect the public’s health by having strong science on which to base regulatory decisions” and “to protect participants in research that it requires.”4Requiring a postmarketing study is an ethical decision, reflecting a weighing of these values.

The committee described the conditions that must be present to justify a decision to require a postmarketing study. The FDA should require postmarketing research only when, first, the uncertainty about the benefit–risk balance of a drug is so great that a responsible decision about its regulatory status cannot be made on the basis of existing evidence; second, the research will reduce this uncertainty; third, the FDA will use the research results expeditiously to make a regulatory decision; and fourth, sufficient protections for research participants can be ensured.

The committee argued that when the FDA requires a postmarketing study, it assumes a measure of ethical responsibility for the welfare of the study participants; exercise of that responsibility cannot be handed off to contractors or the industry sponsor. The responsibility is particularly strong when the patients’ treatment is determined by the study, such as in a randomized trial, linking any adverse outcomes directly to a regulatory decision to require a study of that type. This determination led to one of the most important recommendations from the IOM committee: the responsibilities of the FDA to research participants mean that it should mandate a randomized design only if the FDA “has concluded that an observational study could not provide the necessary information [to help answer the important public health question at issue], that an RCT [randomized, controlled trial] is likely to generate the information within the necessary timeframe, and that the necessary RCT is ethically acceptable.” This recommendation comports with but adds some further conditions to the current legal authority of the FDA under the FDA Amendments Act of 2007, which empowers the agency to require a randomized trial if it cannot obtain the data it needs from an observational study.1

In light of the critiques of the TIDE trial as inherently unethical, the committee addressed the justifiability of trials in which participants may encounter a net increase in risk, as compared with ordinary clinical care, but no realistic prospect of personal benefit. It argued that such trials can be justified only if they are necessary to answer a critically important public health question, if the potential risk is acceptable and minimized, and if special safeguards are in place, including a highly explicit informed-consent process to ensure that patients understand that they are potentially shouldering additional risk solely to contribute to the public good.

Specific actions that the FDA should take to meet its ethical obligations include specifying the study design, title, end points, and primary analyses; identifying design features that it views as ethically and scientifically indispensable; and, for clinical trials, specifying a safety-monitoring scheme. The committee recommended that the FDA routinely communicate with IRBs about required postmarketing studies — for example, by issuing a letter to accompany IRB applications that conveys information that is material to the IRB’s determination of the ethics of the research, as well as providing additional communications over the life of the study as warranted by new information about the drug or by changes in professional practice. The committee also believed that the FDA was ethically obligated to actually use the findings from required studies to make timely regulatory decisions.

The IOM committee emphasized that the adequacy of the informed-consent process is only one element in the ethics of FDA-required postmarketing research. Other central, and indeed prior, features include ensuring that the selection of participants is equitable and that the level of risk to which they are exposed is acceptable. The committee also recognized, however, that there are challenges to achieving meaningful informed consent in postmarketing trials of drugs for which there is a signal indicating the possibility of drug-related harm. In such cases, there is a suspicion that the benefits of the drug may not justify its risks and often that it may have a worse benefit–risk profile than alternative drugs available to treat the same condition. The committee concluded that for postmarketing trials of such drugs, there are “heightened obligations to ensure that potential research participants understand the risks posed by study enrollment.”4 This was of particular importance for rosiglitazone, because the cardiovascular problem it appeared to cause was the same outcome that good diabetic control was supposed to improve — in other words, if this elevation in risk were real, there could be little offsetting benefit.

The committee recommended several measures to strengthen the consent process in order to maximize patients’ understanding of the context in which the trial is being conducted, including what is already known about the risks associated with the drug. The report discussed both specific disclosures in the informed-consent form and special efforts that could be made to ensure adequate comprehension of complex information regarding risks (Table 2TABLE 2Mechanisms for Strengthening the Informed-Consent Process for Postmarketing Drug-Safety Studies.). To assist IRBs, the committee recommended that the FDA issue guidance interpreting current informed-consent regulatory requirements in the context of required postmarketing studies.

STRENGTHENING POSTMARKETING RESEARCH AND ITS GOVERNANCE

Because a true picture of the benefit–risk profile of a drug only emerges over time, two different IOM committees have stressed the need for the FDA to fully embrace a “life-cycle approach” to drug regulation, in which its obligations to protect public health are taken as seriously once a drug is on the market as they are before approval is granted.4,16 Postmarketing regulatory oversight is assuming heightened importance as the FDA accrues additional authority to fast-track drugs for approval on the basis of more limited evidence than was previously required in order to address unmet medical needs and accelerate innovation.17-19 This changing landscape raises several challenges for ensuring the ethical conduct of research with approved drugs and balancing societal interests in drug innovation and drug safety. We highlight two of these challenges here.

First, not all postmarketing research is ethically equivalent. The TIDE trial represented an iconic kind of postmarketing study: an FDA-required randomized trial to study a drug whose benefit–risk profile was under a cloud of suspicion and at a time when alternative treatments were available, albeit not all well studied. The risks to patients of participating in the trial probably outweighed the prospect of direct benefit. By contrast, when the FDA requires an observational study that uses previously collected data, the clinical experience of the participants is unaffected, the risks incurred are not at the behest of the FDA, and ethical concerns are largely confined to confidentiality and the right to control one’s medical information.

Both of these scenarios can be distinguished from the context in which a phase 4 trial is required as a condition of an accelerated drug approval and is initiated soon thereafter. Here, the trial requirement is not imposed because of a newly emerging concern about a drug already in clinical use but because additional evidence is needed to confirm the initial judgment that the benefits of a new drug are likely to outweigh its risks. Often, this initial judgment is based on the use of a surrogate end point for drug benefit, not on the clinical outcomes that matter most. Especially when the new drug targets an unmet medical need, it may be in the patients’ best interest to take it, pending further timely research. The ensuing trial is undertaken to confirm the improvement in clinical outcomes predicted by the surrogate — a different epistemic and ethical situation than that in which substantial evidence suggests that the surrogate is misleading or that other harms might offset a known clinical benefit.

The volume of phase 4 and other research with FDA-approved drugs is increasing, not only because of the expanded authority of the FDA to require such research but also because of the growing volume of comparative-effectiveness research. In some cases, there may be no or little ethical difference between FDA-required postmarketing research and comparative-effectiveness research initiated by academic investigators. By contrast, a comparative-effectiveness study of two widely used drugs that is not occasioned by heightened concern about the risks of one drug relative to the other is markedly different, ethically, from a study required by the FDA to pursue a safety signal that is already of such concern that practice patterns are shifting, even if both studies use randomized designs.

These differences highlight the need for IRBs to be sensitive to the place where a study falls within the life cycle of a drug and to the reason for the research. Depending on who is initiating the research, for what reasons, and when, the same study design may have very different ramifications for the benefit–risk balance of the study and what patients need to know in order to provide meaningful informed consent. Trials that may be regarded as unethical late in the life cycle because of accumulated evidence can be much easier to initiate earlier if the need for additional research is anticipated and planned at the time of initial approval. In the case of rosiglitazone, this need could have been anticipated from preapproval data showing an adverse effect on serum lipids as well as the use of a surrogate end point (glycemic control) for a first-in-class drug.5,20

Second, the experience with rosiglitazone underscored the fragility of our current system of discovering risks associated with drugs. This system relies heavily on drug sponsors and FDA scientists to conduct safety analyses on the basis of data from clinical trials, some or all of which are not publicly available, and to release findings to the public. It has been shown repeatedly that the published record can misrepresent evidence known to the FDA.21,22 In the case of rosiglitazone, scientists from GlaxoSmithKline and the FDA had information from 42 clinical trials, of which only 7 were published and the others were inaccessible. Triggered by concerns expressed by the World Health Organization in 2006, GlaxoSmithKline conducted and shared with the FDA a meta-analysis of the safety of rosiglitazone that used these data, confirming a possibly elevated risk of ischemic events, but neither these results nor the primary trial results were shared with the public until an unrelated court settlement forced GlaxoSmithKline to release its complete clinical-trial data.23 This access led to the published meta-analysis by independent researchers that made these data and concerns public in 2007.5

It is often the work of independent scientists that has highlighted critical safety problems with approved drugs.5,24-29 Yet currently, data from premarketing studies that are submitted as part of a new drug application or a supplemental new drug application are largely shielded from release to external scientists and the public owing to concerns about a competitive disadvantage to drug sponsors.30,31 The IOM committee stopped short of calling on the FDA to increase public access to such data but recommended that the agency initiate a process to determine ways to “appropriately balance public health, privacy, and proprietary interests to facilitate disclosure” of relevant data.4 Greater transparency would better equip independent scientists to investigate early safety signals.31 Consideration should be given to making drug-safety data from clinical trials available to the public on request once the FDA has reached a decision regarding a new drug application or a supplemental new drug application or once the manufacturer has abandoned the application, unless the manufacturer can articulate a persuasive reason why it would result in competitive harm and the FDA determines that this harm outweighs the public health benefits of releasing the information.

CONCLUSIONS

The experience with rosiglitazone and the TIDE trial offers a lesson in how our current approach to the oversight of drug-safety and postmarketing research can fail both the public and the research participants. Although terminating the TIDE trial was justifiable, it left regulators with highly suggestive but nondefinitive data on the relative safety of rosiglitazone and the closest clinical alternative, pioglitazone.32

Reactive policymaking is tempting but problematic. The history of regulation of human subjects research suggests that rules that are “born in scandal and reared in protectionism”33 often fall short of providing meaningful protections to research participants and that, once adopted, regulations can ossify and become difficult to dislodge. Nevertheless, the IOM committee’s report makes a number of actionable recommendations that the FDA can implement under its existing authority.34 In addition, appointment of an independent ethics advisory board would strengthen the decision making of the FDA as it confronts emerging ethical challenges — both those arising from required postmarketing trials and those stemming from powerful new drug surveillance systems, such as the FDA’s Sentinel Initiative. As the pace of the translation of discoveries from bench to bedside continues to intensify, so too does the imperative for thoughtful ethical governance throughout the life cycle of a drug.

The views expressed in this article are those of the authors and, except where noted, do not represent the official position of the Institute of Medicine or of the committee that produced the report discussed in this article.

Drs. Faden and Goodman chaired, and Dr. Mello was a member of, the Institute of Medicine committee that produced the report discussed in this article.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on August 22, 2012, at NEJM.org.

We thank the other IOM committee members for contributing to some of the ideas discussed.

SOURCE INFORMATION

From the Department of Health Policy and Management, Harvard School of Public Health, Boston (M.M.M.); the Departments of Medicine and Health Research and Policy, Stanford University School of Medicine, Stanford, CA (S.N.G.); and the Berman Institute of Bioethics, Johns Hopkins University, Baltimore (R.R.F.).

REFERENCES

    1. 1Food and Drug Amendments Act of 2007, Pub. L. No. 110-85, 121 Stat. 823. (2007).

    1. 2London AJ, Kimmelman J, Carlisle B. Research ethics: rethinking research ethics: the case of postmarketing trials. Science 2012;336:544-545
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    1. 3ClinicalTrials.gov. Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE). 2011 (http://clinicaltrials.gov/ct2/show/NCT00879970?term=NCT00879970&rank=1).

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      http://www.nejm.org/doi/full/10.1056/NEJMhle1207160?query=TOC

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