Pharma’s Cutting Edge

Every so often, I like to pick apart a company press release for analysis.  Primarily I do this for the educational opportunity, not only for my readers but also for me.  It’s a good way to catch up to what’s happening in a hot therapeutic area if nothing else.  I’ve chosen Human Genome Sciences and GlaxoSmithKline’s Announcement   of their initiation of a Phase 3 clinical trial of LymphoStat-B (belimumab) in Systemic Lupus Erythematosus (SLE).  I have no financial stakes in either company.

HGS is a hot biotech company that was one of the pioneers (along with Incyte, Millennium et al) in decoding the human genome’s expressed sequences.  They’re now trying to become a therapeutics company and are partnered since August 2006 with GSK in the development and eventually the marketing of LymphoStat-B.  The drug is a recombinantly expressed human monoclonal antibody, developed by HGS in collaboration with Cambridge Antibody Technologies (now part of AstraZeneca), that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS.  BLyS is a naturally occurring protein discovered by HGS that is required for the development of B-lymphocyte cells into mature plasma B cells.  In autoimmune diseases, such as SLE, elevated levels of BLyS are believed to contribute to the production of autoantibodies.

SLE is a chronic, often debilitating disease, that affects primarily younger women. In the US, about 1.5 million people have some form of lupus; a major organ is involved in about 35% of these people. Although improved care of SLE has resulted in extensions of lifespan, current therapies are inadequate to prevent substantial morbidities, including endstage organ failure, most commonly kidney failure, from occurring in substantial numbers of patients.  The subset of SLE patients with major organ involvement and active serology (i.e. autoantibodies in the blood) are the people who might eventually benefit from treatment Lymphostat-B.

The US FDA has a published a draft clinical guidance for development of drugs to treat SLE, and I’ll refer to this in my comments on the announcement.

Here’s the meat of the press release, re-ordered a bit to enhance comprehension and with my commentary offset by brackets in italics:

LymphoStat-B was generated by HGS through a collaboration with Cambridge Antibody Technology. It has received a Fast Track Product designation from the FDA for its potential use in treating SLE and has been selected for participation in the FDA’s Continuous Marketing Application Pilot 2 Program. The FDA has provided a Special Protocol Assessment agreeing to the LymphoStat- B Phase 3 clinical development program in patients with active SLE. [[I’m providing links to FDA descriptions of these programs in lieu of an extensive discussion.  See also my paper on the Fast Track Effect.  Basically, HGS took advantage of FDA’s willingness to give feedback and prior assurances to innovators of potentially life-altering medicines.  HGS can now be reasonably sure that if Lymphostat-B proves to be effective and safe in Phase 3 that they will be able to make certain pre-specified claims about the drug in their promotions.]]  Agreement has also been received from the European Agency for the Evaluation of Medicinal Products (EMEA) on the major components of the LymphoStat-B Phase 3 clinical development program, including the primary efficacy endpoint measures, target patient population, and dose selection. [[Seeing that they were falling behind the FDA in the quantity and quality of pre-submission advice being offered to applicants, EMEA improved its scientific advice program formally in April 2006.  Product claims made in European countries are still subject to much more political influence than in the US, but HGS can be reasonably sure that its Phase 3 study designs will allow for EMEA approval of marketing in member states assuming the drug is safe and effective.  Generally speaking, sponsors should avail themselves of both FDA’s and EMEA’s scientific advice opportunities whenever they make key product-development decisions (such as the Phase 3 decision).  I’ve met more than one small-firm chief that seemed offended at the idea of taking FDA’s scientific advice.  Offended or not, just get the advice and take it very seriously.]] Read the rest of this entry »

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Will post some stories that happened while I was away from the office. This first one is from Randall Willis at DDN, who reports that the EMEA and FDA will jointly review and comment upon Voluntary Genomic Data Submissions (VGDS). This is fairly big news that received virtually no media attention, perhaps because observers have become accustomed to collaboration between FDA and EMEA via the ICH process. But this is different. ICH provides a framework for submission of regulatory documents. It does not provide for joint agency review and commentary, as does this VGDS initiative. Willis raises the issue of creation of a superagency, with VGDS as a first step. I don’t see broader review and commentary collaboration becoming the norm anytime soon, given legislative inertia on both sides. But I like this relatively innocuous collaboration as a test of how collaboration might look sometime in the distant future.

For this month’s PCE column, I wanted to say something about interim analyses. They’re in the news nearly every day, attesting to their importance, and yet they are not well understood by most people in the industry, the academic community or lay public. Problem is, there’s a lot to say about interim analyses, and I don’t want to short-change the topic. My compromise is to discuss the Data Monitoring Committee (or DMC) this month and save other interim-analysis topics for a future article(s). The primary references are FDA’s March 2006 final guidance on DMCs and EMEA’s (i.e. CHMP) 2005 guideline on DMCs. If you are going to pick only one of these documents to read, I can recommend the EMEA doc for its brevity and the FDA doc for its thoroughness. I would imagine that ICH has some interest in providing a harmonized guideline, but they apparently have higher priority issues to tackle.

DMCs were first used in the 1960s in NIH-sponsored clinical trials. The rationale for the DMC then (when they were primarily referred to as Data and Safety Monitoring Boards, or DSMBs) was the same as it is now: minimize trial operational biases by using sponsor-independent personnel to monitor study integrity and subject safety. But you might have heard the term Independent DMC. Sounds redundant according to the aforementioned rationale, doesn’t it? It’s not. At some point during evolution of the DMC, probably when industry started to sponsor large clinical trials and senior executives began getting cryptic recommendations on their most important investigational drugs from scientific groups without ties to industry, sponsors decided that it probably wasn’t in their interests to let independent DMCs run their pivotal-trial interim analyses. At that time, industry sponsors relaxed the composition of DMCs to include their own employees. Sometimes these employees were behind a “firewall” to minimize study bias. However, it was not unusual for sponsor employees directly involved in trial design, conduct and final analysis to supervise DMC activities, particularly for non-pivotal studies.

Fairly recently, though, the pendulum has swung back towards industry-sponsor independence for DMC members. The reason is simply that investigators in larger trials with “hard” outcomes (e.g. mortality) didn’t look kindly upon industry sponsors as the primary overseers of trial subject safety and study integrity, and neither did regulators. Quite frankly, had industry enjoyed a sterling reputation during the 1990’s, I have little doubt that the pendulum would have stayed where it was. The call for independent DMCs (and independent steering and endpoint committees) is simply another manifestation of the public’s general distrust of anything the industry sponsors. In any case, thus was born again the truly independent DMC, a DMC composed entirely or nearly entirely of non-sponsor personnel. When the sponsor has a member on an independent DMC, he or she usually plays an administrative or oversight role only, without a vote and with limited access to data.

FDA describes factors leading to the increasing use of DMCs today:

• The growing number of industry-sponsored trials with mortality or major morbidity endpoints;
• The increasing collaboration between industry and government in sponsoring major clinical trials, resulting in industry trials performed under the policies of government funding agencies, which often require DMCs;
• Heightened awareness within the scientific community of problems in clinical trial conduct and analysis that might lead to inaccurate and/or biased results, especially when early termination for efficacy is a possibility, and need for approaches to protect against such problems;
• Concerns of IRBs regarding ongoing trial monitoring and patient safety in multicenter trials.

Implicit in the above factors is increasing pressure on industry sponsors to relinquish more of their direct control over clinical-trial design, conduct and analysis. Pressure to use DMCs is just one reflection of this bigger trend. Independent steering committees, publication committees, endpoint committees, etc are others.

There is no U.S. law mandating use of DMCs, except in the emergency-use setting, when informed consent of the participant is excepted [21 CFR 50.24(a)(7)(iv)]. FDA recommends use of a DMC for: “any controlled trial of any size that will compare rates of mortality or major morbidity…DMCs are generally not needed, [however], for trials at early stages of product development.” Let’s just spend a moment on this point. Is FDA not recommending a DMC for most studies because a DMC would not be useful, or because a DMC is not worth the additional effort necessary to implement given its value in early-phase studies? I believe that FDA’s recommendation is based on the value proposition. In other words, this is FDA’s judgment, based on their sense of the value of a DMC to the study sponsor. IRBs, investigators and other regulators might well have differing judgments from FDA. It is crucial for a sponsor to consider these other opinions prior to determining finally whether to implement a DMC, regardless of phase of development. Indeed, phase of development has different meanings for different therapy areas and study designs. [Example: A Phase 2 oncology trial might have a mortality endpoint, whereas a Phase 2 hypertension trial likely will have a blood pressure endpoint.]

FDA goes on to refine the decision drivers for implementing a DMC:

• The study endpoint is such that a highly favorable or unfavorable result, or even a finding of futility, at an interim analysis might ethically require termination of the study before its planned completion;
• There are a priori reasons for a particular safety concern, as, for example, if the procedure for administering the treatment is particularly invasive;
• There is prior information suggesting the possibility of serious toxicity with the study treatment;
• The study is being performed in a potentially fragile population such as children, pregnant women or the very elderly, or other vulnerable populations, such as those who are terminally ill or of diminished mental capacity;
• The study is being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser endpoint;
• The study is large, of long duration, and multi-center.

FDA’s decision framework makes a lot of sense to me. The bottom line to ask yourself as a sponsor: Would a DMC help mitigate risk to subjects, where the potential risk to subjects is potentially only marginally outweighed by potential benefit? Would a DMC help maintain study integrity? If either of these two questions is answered by “Yes” strongly consider using a DMC.

So, who should be on the DMC, and what is the correct number of members? To the latter, keep the number as small as feasible while making sure to have the appropriate expertise on board. FDA says three is a minimum number. I would say that three is generally too few; four provides a margin of safety to cover unforseeable absences. These numbers don’t include personnel necessary to administer all DMC activities (i.e. logistics). The DMC constituency should include: a Chair (who can appoint the other members and is responsible for communications beyond the DMC), one or more statisticians (to perform and/or assist in interpetation of data analyses), clinicians (therapeutic area and/or clinical research experts), and others. Among the “others” to consider, FDA suggests epidemiologists and non-scientists with interest in the study outcome. I consider these reasonable suggestions. Finally, it’s important to assess potential conflicts of interest when deciding whom to appoint to a DMC. Here’s FDA suggestion for doing this:

• Ensure that those with serious conflicts of interest are not included on the DMC;
• Provide disclosure to all DMC members of any potential conflicts that are not thought to impede objectivity and thus would not preclude service on the DMC;
• Identify and disclose any concurrent service of any DMC member on other DMCs of the same, related or competing products.

Once a sponsor determines to form a DMC (and who will administer it–for a large pivotal study strongly consider outsourcing DMC administration), the first step is to create a DMC Charter. The Charter is essentially a contract between the DMC and the sponsor. It describes the DMC mission, membership, and all operating procedures. One of the key parts of this Charter is how data will be shared between the sponsor and the DMC.

FDA describes how this should operate ideally. Basically, the sponsor and its personnel should remain blinded to all comparative data in a blinded trial: “We recommend that any part of the interim report to the DMC that includes comparative effectiveness and safety data presented by study group, whether coded or completely unblinded, be available only to DMC members during the course of the trial, including any follow-up period—that is, until the trial is completed and the blind is broken for the sponsor and investigators.” The way this accomplished easily is by creating a sponsor-indepedent data analysis group (another reason why outsourcing is a good idea). Short of this, create a data-analysis group within the sponsor that isn’t otherwise involved with the study design or conduct. Read the rest of this entry »

BioPartners failed to impress the CHMP with its biosimilar application for Alpheon, a biosimilar to Roferon A. Had Alpheon been approved, it would have marked the first non-GH biosimilar approval in Europe. This case demsnstrates some of the technical hurdles that must be cleared to receive EU approval. I would expect that similar issues would be raised by FDA for a Roferon-A biosimilar in the U.S. submitted via the 505(b)(2) path. If anything, FDA is likely to be stricter than the CHMP. I’ve followed the biosimilar story closely for the past three years and will continue to keep you updated on its evolution. If your firm sells recombinant products, there is no single issue more likely to change your firm’s long-term prospects than this one.

I had kind of an “interesting” morning. I use that word because I don’t have a “nice day” anymore. Frankly, I don’t bother with them. I feel as if I’ve outgrown the nice day. Why should I be hogging all the really nice ones? –George Carlin

Let’s hope Pfizer was in the mood for a really crappy day on or about April 13th, because that’s what NICE delivered to them in the form of a technology evaluation report for the recently approved inhaled insulin, Exubera. The nice thing for readers of this blog is that this month I’ll review the NICE decision to see whether it was at least fair, if not nice, and what other companies might take away from it.

Readers, please note that I will put a PDF copy of this post on the PGS library, which will serve as a repository for selected blog posts of broad interest. Eventually, I’ll set up a mailing list, so that readers can receive notices of updates to the library.

One of the points that should strike any reader of the assessment report at the very outset is that Pfizer spends more than any pharma on R&D, and they didn’t slouch on the development of Exubera. Indeed, the development program was more than adequate for regulatory approval and was clearly designed with pricing and reimbursement in mind. Yet, Pfizer failed to make a positive impression with the hard-to-please NICE reviewers: Corri Black, Ewen Cummins, Pam Royle, Sam Philip and Norman Waugh. Skeptics will argue that NICE’s decision was pre-ordained and that they fudged the numbers in their evaluation to make the data fit their preferred outcome. I usually count myself among the skpetics, but I will instead argue that one of NICE’s mandates is to place the burden of proof for incremental cost effectiveness (ICE) squarely on the shoulders of the sponsor; they have no mandate to give sponsors the benefit of the doubt in their independent assessment.

To save time and space, I’m not going to summarize the entire NICE report. Instead, I’ll point you to the brief overview document and ask you to read that prior to continuing. I’m also not going to dwell on details of the economic arguments made by either side. Rather, I’m going to focus on reasons NICE used to accept or reject the assumptions and data from the sponsor for economic modeling, because these assumptions and data drive the modeling results and thus the final decision. Sponsors have control over the design, conduct, analysis and reporting of economic-supporting studies. They do not have control over the assumptions NICE or other independent agents use for their ICE models, but they do have the ability to adequately justify and support the choice of their own assumptions. So, did Pfizer spend their money wisely? Where could they have done more or better during study design and execution? What might they have done differently during reporting? Most importantly, is it feasible to demonstrate the ICE of new drugs prior to first launch, or should sponsors instead focus on approval and enough ICE evidence to get high co-pay (e.g. Tier 3) coverage in the U.S. and limited to no coverage in Europe?

NICE Conclusions and Arguments
Background Information from NICE of Special Importance to NICE Opinion

1. As Type 2 diabetes [N.B. Type 2 diabetes, because of its much higher prevalence than Type 1, accounts for roughly 80% of all insulin users in the U.S. and U.K. and an even higher proportion of insulin doses administered] severity (as reflected by HbA1c) changes, the relative significance of fasting and pre-prandial versus post-prandial glucose levels likewise changes. At low HbA1c levels, post-prandial glucose accounts for up to 70% of HbA1c elevation; at HbA1c levels above 8.4, fasting and pre-prandial glucose account for the majority of HbA1c elevation. This is important for Exubera, because it is a short-acting insulin that primarily affects post-prandial glucose. 
2. Type 2 diabetes progresses, and most patients will eventually require exogenous insulin. In the UKPDS (the largest prospective, controlled study of Type 2 diabetes), only a small proportion of patients who required insulin refused it.
3. Exubera has a short-acting profile and would not, therefore, remove the need for a long-acting insulin injection for nearly all patients who might require insulin (assuming a stepwise approach to insulin therapy, where insulin is a therapy of last-resort).
4. Use of Exubera would not obviate the need for self-monitoring of blood glucose.
5. Given above, NICE limited its review to just three clinical scenarios where the use of Exubera would be considered “reasonable”: as an alternative to short-acting injected insulin in Type 1 diabetes; as an alternative to injected insulin regimens in Type 2 patients failing maximal oral therapy; as an alternative to intensifying the insulin regimen in Type 2 patients failing once-daily long-acting insulin.

Safety and Effectiveness of Inhaled Insulin

1. Inhaled insulin is clinically effective, and is as good as short-acting soluble (i.e. regular) insulin in controlling blood glucose. 
2. The frequency of hypoglycaemia is similar to regular insulin.
3. Long-term studies are needed to rule out uncommon but serious adverse effects of inhaled insulin on the lung.
4. None of the published trials have compared Exubera with short-acting injected analogs.
5. Clinical trial subjects used combinations of short-acting, and either long or intermediate-acting insulin, and both were changed, making it more difficult to assess the change from soluble (i.e. injected) to inhaled. 

Patient Preference

1. Most patients preferred inhaled to injected short-acting, but bias due to trial design could have impacted this finding
2. The sponsor provided no evidence to support the assumption that a switch to insulin would be more acceptable if inhaled insulin was an option, yet used this assumption in their models. 

Cost-Effectiveness

1. Sponsor’s model is high-quality, but their key assumptions (QOL improvement size and acceptability of switch to insulin—see #2 under “Patient Preference) are not supported by the evidence; the ICE results depend more on the assumptions than the model. 
2. The cost of inhaled insulin will be much higher than injected.
3. Inhaled insulin is unlikely to be cost-effective. Read the rest of this entry »
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